ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 156 GDREGFLWKRGRDNSQFLRRRFVLLSREGLLKYYTKEEGKTPKAIINIKDLNATFQTEKIGHPHGLQITYRKEGQTRNLF 235
Cdd:cd13252     1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEDAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                          90       100
                  ....*....|....*....|....*....
gi 1958660592 236 VYHDSGKEIVDWFNALRAARLQYLKLAFP 264
Cdd:cd13252    81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 278 NYLKQGFMEKTGPKHREPFKKRWFALDpqERRLLYYKNPLDAFEQGQVFLGSNEQGYEVWEGLPQGIRGnRWKVGLTVIT 357
Cdd:cd01251     1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1958660592 358 PERKFVFTCPTEKEQREWLESLRGVLSS 385
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 156 GDREGFLWKRGRDNSQFLRRRFVLLSREGLLKYYTKEEGKTPKAIINIKDLNATFQTEKIGHPHGLQITYRKEGQTRNLF 235
Cdd:cd13252     1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEDAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                          90       100
                  ....*....|....*....|....*....
gi 1958660592 236 VYHDSGKEIVDWFNALRAARLQYLKLAFP 264
Cdd:cd13252    81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 278 NYLKQGFMEKTGPKHREPFKKRWFALDpqERRLLYYKNPLDAFEQGQVFLGSNEQGYEVWEGLPQGIRGnRWKVGLTVIT 357
Cdd:cd01251     1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1958660592 358 PERKFVFTCPTEKEQREWLESLRGVLSS 385
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

Putative GTP-ase activating proteins for the small GTPase, ARF; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592   12 LELLQAAgTGNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRN-FPDISKVKSVRL 90
Cdd:smart00105   1 LKLLRSI-PGNKKCFDCGAP------------------------NPTWASVNLGVFLCIECSGIHRSlGVHISKVRSLTL 55

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958660592   91 DFWDDSMVEFMTHNGNLSVKAKFEARVPTFYYVPQASDCLVLKEQWIRAKYERQEF 146
Cdd:smart00105  56 DTWTEEELRLLQKGGNENANSIWESNLDDFSLKPPDDDDQQKYESFIAAKYEEKLF 111

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  280 LKQGFMEKTGPKHREPFKKRWFALDpqERRLLYYKNP---LDAFEQGQVFLgsneQGYEVWEGLPQGIRGNRWkvGLTVI 356
Cdd:smart00233   2 IKEGWLYKKSGGGKKSWKKRYFVLF--NSTLLYYKSKkdkKSYKPKGSIDL----SGCTVREAPDPDSSKKPH--CFEIK 73

                           90       100
                   ....*....|....*....|....*....
gi 1958660592  357 TPERK-FVFTCPTEKEQREWLESLRGVLS 384
Cdd:smart00233  74 TSDRKtLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 158 REGFLWKRGRDNSQFLRRRFVLLSREGLL--KYYTKEEGKTPKAIINIKDL--NATFQTEKIGHPHGLQITYRKEGQTRN 233
Cdd:pfam00169   3 KEGWLLKKGGGKKKSWKKRYFVLFDGSLLyyKDDKSGKSKEPKGSISLSGCevVEVVASDSPKRKFCFELRTGERTGKRT 82

                          90       100
                  ....*....|....*....|.
gi 1958660592 234 LFVYHDSGKEIVDWFNALRAA 254
Cdd:pfam00169  83 YLLQAESEEERKDWIKAIQSA 103

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  56 DPDWASYKLGVFICLHCSGVHRNFP-DISKVKSVRLDFWDDSMVEFMTHNGNLSVKAKFE 114
Cdd:PLN03114   32 NPTWASVTYGIFLCIDCSAVHRSLGvHISFVRSTNLDSWSSEQLKMMIYGGNNRAQVFFK 91

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 156 GDREGFLWKRGRDNSQFLRRRFVLLSREGLLKYYTKEEGKTPKAIINIKDLNATFQTEKIGHPHGLQITYRKEGQTRNLF 235
Cdd:cd13252     1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEDAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                          90       100
                  ....*....|....*....|....*....
gi 1958660592 236 VYHDSGKEIVDWFNALRAARLQYLKLAFP 264
Cdd:cd13252    81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

ArfGap with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592   5 ERNKKRLLELLQAagTGNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNFPD-IS 83
Cdd:cd08832     2 ERNKKRLLELLKL--PGNNTCADCGAP------------------------DPEWASYNLGVFICLDCSGIHRSLGThIS 55

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1958660592  84 KVKSVRLDFWDDSMVEFMTHNGNLSVKAKFEARVPTFYYVPQASDCLVLKEQWIRAKY 141
Cdd:cd08832    56 KVKSLRLDNWDDSQVEFMEENGNEKAKAKYEAHVPAFYRRPTPTDPQVLREQWIRAKY 113

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 278 NYLKQGFMEKTGPKHREPFKKRWFALDpqERRLLYYKNPLDAFEQGQVFLGSNEQGYEVWEGLPQGIRGnRWKVGLTVIT 357
Cdd:cd01251     1 DFLKEGYLEKTGPKQTDGFRKRWFTLD--DRRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1958660592 358 PERKFVFTCPTEKEQREWLESLRGVLSS 385
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

Putative GTPase activating protein for Arf; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592   8 KKRLLELLQAAGtgNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNF-PDISKVK 86
Cdd:pfam01412   1 KRVLRELLKLPG--NKVCADCGAP------------------------NPTWASVNLGIFICIDCSGVHRSLgVHISKVR 54

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  87 SVRLDFWDDSMVEFMTHNGNLSVKAKFEARVPTFYYvPQASDCLVLKEQWIRAKYERQEF 146
Cdd:pfam01412  55 SLTLDTWTDEQLELMKAGGNDRANEFWEANLPPSYK-PPPSSDREKRESFIRAKYVEKKF 113

Stromal membrane-associated proteins; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  11 LLELLQAagTGNGHCADCGAAGPAcpctlvqslsssaeillfhpadpdWASYKLGVFICLHCSGVHRNF-PDISKVKSVR 89
Cdd:cd08839     1 LAKLLRE--EDNKYCADCGAKGPR------------------------WASWNLGVFICIRCAGIHRNLgVHISKVKSVN 54

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1958660592  90 LDFWDDSMVEFMTHNGNLSVKAKFEARVPTFYYVPQASDCLvlkEQWIRAKY 141
Cdd:cd08839    55 LDSWTPEQVQSMQEMGNARANAYYEANLPDGFRRPQTDSAL---ENFIRDKY 103

ArfGAP domain of ACAP (ArfGAP with Coiled-coil, ANK repeat and PH domains) proteins; ArfGAP domain is an essential part of ACAP proteins that play important role in endocytosis, actin remodeling and receptor tyrosine kinase-dependent cell movement. ACAP subfamily of ArfGAPs are composed of coiled coils (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. In addition, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages. ACAP3 also positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  21 GNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNFP-DISKVKSVRLDFWDDSMVE 99
Cdd:cd08835    12 GNAQCCDCGSP------------------------DPRWASINLGVTLCIECSGIHRSLGvHVSKVRSLTLDSWEPELLK 67

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1958660592 100 FMTHNGNLSVKAKFEARVPTFYYVPQASDC-LVLKEQWIRAKYERQEFM 147
Cdd:cd08835    68 VMLELGNDVVNRIYEANVPDDGSVKPTPDSsRQEREAWIRAKYVEKKFV 116

Stromal membrane-associated protein 2; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  22 NGHCADCGAAGPAcpctlvqslsssaeillfhpadpdWASYKLGVFICLHCSGVHRNFP-DISKVKSVRLDFWDDSMVEF 100
Cdd:cd08859    10 NKFCADCQSKGPR------------------------WASWNIGVFICIRCAGIHRNLGvHISRVKSVNLDQWTQEQIQC 65

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1958660592 101 MTHNGNLSVKAKFEARVPTFYYVPQASDCLvlkEQWIRAKYERQE 145
Cdd:cd08859    66 MQEMGNGKANRLYEAFLPENFRRPQTDQAV---EGFIRDKYEKKK 107

ArfGAP with GTPase domain, ANK repeat and PH domain 3; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  21 GNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNF-PDISKVKSVRLDFWDDSMVE 99
Cdd:cd08855    13 GNSFCIDCDAP------------------------NPDWASLNLGALMCIECSGIHRNLgTHLSRVRSLDLDDWPVELSM 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1958660592 100 FMTHNGNLSVKAKFEARVPTfYYVPQASDCLVLKEQWIRAKYE 142
Cdd:cd08855    69 VMTAIGNAMANSVWEGALDG-YSKPGPDSTREEKERWIRAKYE 110

ArfGAP domain of ACAP3 (ArfGAP with Coiled-coil, ANK repeat and PH domains 3); ACAP3 belongs to the ACAP subfamily of GAPs (GTPase-activating proteins) for the small GTPase Arf (ADP-ribosylation factor). ACAP subfamily of ArfGAPs are composed of Coiled coli (BAR, Bin-Amphiphysin-Rvs), PH, ArfGAP and ANK repeats domains. It has been shown that ACAP3 positively regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons. ACAP1 (centaurin beta1) and ACAP2 centaurin beta2) also have a GAP (GTPase-activating protein) activity preferentially toward Arf6, which regulates endocytic recycling. Both ACAP1/2 are activated by are activated by the phosphoinositides, PI(4,5)P2 and PI(3,5)P2. ACAP1 binds specifically with recycling cargo proteins such as transferrin receptor (TfR) and cellubrevin. Thus, ACAP1 promotes cargo sorting to enhance TfR recycling from the recycling endosome. In addition, phosphorylation of ACAP by Akt, a serine/threonine protein kinase, regulates the recycling of integrin beta1 to control cell migration. In contrast, ACAP2 does not exhibit a similar interaction with the recycling cargo proteins. It has been shown that ACAP2 functions both as an effector of Ras-related protein Rab35 and as an Arf6-GTPase-activating protein (GAP) during neurite outgrowth of PC12 cells. Moreover, ACAP2, together with Rab35, regulates phagocytosis in mammalian macrophages.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  11 LLELLQAAgTGNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNFP-DISKVKSVR 89
Cdd:cd08850     3 ILQRVQSI-AGNDQCCDCGQP------------------------DPRWASINLGILLCIECSGIHRSLGvHCSKVRSLT 57

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958660592  90 LDFWDDSMVEFMTHNGNLSVKAKFEARVPTF-YYVPQASDCLVLKEQWIRAKYERQEFM 147
Cdd:cd08850    58 LDSWEPELLKLMCELGNSTVNQIYEAQCEELgLKKPTASSSRQDKEAWIKAKYVEKKFL 116

ArfGAP with GTPase domain, ANK repeat and PH domain 2; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  21 GNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNF-PDISKVKSVRLDFWDDSMVE 99
Cdd:cd08853    12 GNSHCVDCETQ------------------------NPKWASLNLGVLMCIECSGIHRNLgTHLSRVRSLDLDDWPVELRK 67

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1958660592 100 FMTHNGNLSVKAKFEARVPTfYYVPQASDCLVLKEQWIRAKYE 142
Cdd:cd08853    68 VMSSIGNELANSIWEGSSQG-QTKPSSDSTREEKERWIRAKYE 109

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  21 GNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNF-PDISKVKSVRLD--FWDDSM 97
Cdd:cd08837    12 ANRFCADCGAP------------------------DPDWASINLCVVICKQCAGEHRSLgSNISKVRSLKMDtkVWTEEL 67

                          90       100
                  ....*....|....*....|.
gi 1958660592  98 VEFMTHNGNLSVKAKFEARVP 118
Cdd:cd08837    68 VELFLKLGNDRANRFWAANLP 88

Arf1 GTPase-activating protein 2/3-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592   5 ERNK--KRLLELlqaagTGNGHCADCGAAGPacpctlvqslsssaeillfhpadpDWASYKLGVFICLHCSGVHRNF-PD 81
Cdd:cd08831     1 ERDAifKKLRSK-----PENKVCFDCGAKNP------------------------TWASVTFGVFLCLDCSGVHRSLgVH 51

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958660592  82 ISKVKSVRLDFWDDSMVEFMTHNGNLSVKAKFE 114
Cdd:cd08831    52 ISFVRSTNLDSWTPEQLRRMKVGGNAKAREFFK 84

ArfGAP domain of the AGFG subfamily (ArfGAP domain and FG repeat-containing proteins); The ArfGAP domain and FG repeat-containing proteins (AFGF) subfamily of Arf GTPase-activating proteins consists of the two structurally-related members: AGFG1 and AGFG2. AGFG1 (alias: HIV-1 Rev binding protein, HRB; Rev interacting protein, RIP; Rev/Rex activating domain-binding protein, RAB) and AGFG2 are involved in the maintenance and spread of immunodeficiency virus type 1 (HIV-1) infection. The ArfGAP domain of AGFG is related to nucleoporins, which is a class of proteins that mediate nucleocytoplasmic transport. AGFG plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs, possibly together by the nuclear export receptor CRM1. In humans, the presence of the FG repeat motifs (11 in AGFG1 and 7 in AGFG2) are thought to be required for these proteins to act as HIV-1 Rev cofactors. Hence, AGFG promotes movement of Rev-responsive element-containing RNAs from the nuclear periphery to the cytoplasm, which is an essential step for HIV-1 replication.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592   9 KRLLELLQAAGtgNGHCADCGAAGPACPCTlvqslsssaeillfhpadpdwasyKLGVFICLHCSGVHRNFPdiSKVKSV 88
Cdd:cd08838     2 KILRELLKLPE--NKRCFDCGQRGPTYVNL------------------------TFGTFVCTTCSGIHREFN--HRVKSI 53

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958660592  89 RLDFWDDSMVEFMTHNGNLSVKAKFEARV-PTFYYVPQASDCLVLKEqWIRAKYERQEFMA 148
Cdd:cd08838    54 SMSTFTPEEVEFLQAGGNEVARKIWLAKWdPRTDPEPDSGDDQKIRE-FIRLKYVDKRWYD 113

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  21 GNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNFP-DISKVKSVRLDFWDDSMVE 99
Cdd:cd08959    13 ENKVCFDCGAK------------------------NPQWASVTYGIFICLDCSGVHRGLGvHISFVRSTTMDKWTEEQLR 68

                          90
                  ....*....|....*.
gi 1958660592 100 FMTHNGNLSVKAKFEA 115
Cdd:cd08959    69 KMKVGGNANAREFFKQ 84

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 2; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP2 localizes to the cell periphery and on focal adhesions composed of paxillin and vinculin, and functions downstream of RhoA to regulate focal adhesion dynamics. ARAP2 is a PI(3,4,5)P3-dependent Arf6 GAP that binds RhoA-GTP, but it lacks the predicted catalytic arginine in the RhoGAP domain and does not have RhoGAP activity. ARAP2 reduces Rac1oGTP levels by reducing Arf6oGTP levels through GAP activity. AGAP2 also binds to and regulates focal adhesion kinase (FAK). Thus, ARAP2 signals through Arf6 and Rac1 to control focal adhesion morphology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  22 NGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNF-PDISKVKSVRLD--FWDDSMV 98
Cdd:cd08856    18 NRSCADCKAP------------------------DPDWASINLCVVICKKCAGQHRSLgPKDSKVRSLKMDasIWSNELI 73

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1958660592  99 EFMTHNGNLSVKAKFEARVPTFYYVPQASDcLVLKEQWIRAKYERQEF 146
Cdd:cd08856    74 ELFIVVGNKPANLFWAANLFSEEDLHMDSD-VEQRTPFITQKYKEGKF 120

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  280 LKQGFMEKTGPKHREPFKKRWFALDpqERRLLYYKNP---LDAFEQGQVFLgsneQGYEVWEGLPQGIRGNRWkvGLTVI 356
Cdd:smart00233   2 IKEGWLYKKSGGGKKSWKKRYFVLF--NSTLLYYKSKkdkKSYKPKGSIDL----SGCTVREAPDPDSSKKPH--CFEIK 73

                           90       100
                   ....*....|....*....|....*....
gi 1958660592  357 TPERK-FVFTCPTEKEQREWLESLRGVLS 384
Cdd:smart00233  74 TSDRKtLLLQAESEEEREKWVEALRKAIA 102

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single PH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 154 PPGDREGFLWKRGRDNSQFLRRRFVLlsREGLLKYYTKEEGKTPKAIINIKdlNATFQTEKIGHPHGLQITYRKEGqTRN 233
Cdd:cd13288     6 SPVDKEGYLWKKGERNTSYQKRWFVL--KGNLLFYFEKKGDREPLGVIVLE--GCTVELAEDAEPYAFAIRFDGPG-ARS 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958660592 234 LFVYHDSGKEIVDWFNALRAARLQYLKLAFPDL 266
Cdd:cd13288    81 YVLAAENQEDMESWMKALSRASYDYLRLTVEEL 113

TBC1 domain family member 2A pleckstrin homology (PH) domain; TBC1D2A (also called PARIS-1/Prostate antigen recognized and identified by SEREX 1 and ARMUS) contains a PH domain and a TBC-type GTPase catalytic domain. TBC1D2A integrates signaling between Arf6, Rac1, and Rab7 during junction disassembly. Activated Rac1 recruits TBC1D2A to locally inactivate Rab7 via its C-terminal TBC/RabGAP domain and facilitate E-cadherin degradation in lysosomes. The TBC1D2A PH domain mediates localization at cell-cell contacts and coprecipitates with cadherin complexes. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 279 YLkqGFMEKTGPKHREpFKKRWFALDPQERRLLYYKNPLDAFEQGQVFLGSNEQGYEVWEGlpQGIrgnrwkvgLTVITP 358
Cdd:cd01265     5 YL--NKLETRGLGLKG-WKRRWFVLDESKCQLYYYRSPQDATPLGSIDLSGAAFSYDPEAE--PGQ--------FEIHTP 71

                          90       100
                  ....*....|....*....|.
gi 1958660592 359 ERKFVFTCPTEKEQREWLESL 379
Cdd:cd01265    72 GRVHILKASTRQAMLYWLQAL 92

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592 281 KQGFMEKTGPKHREPFKKRWFALdpQERRLLYYKNPL---DAFEQGQVFLGSNEQGYEVweGLPQGIRGNRWKVGLTVIT 357
Cdd:pfam00169   3 KEGWLLKKGGGKKKSWKKRYFVL--FDGSLLYYKDDKsgkSKEPKGSISLSGCEVVEVV--ASDSPKRKFCFELRTGERT 78

                          90       100
                  ....*....|....*....|....*..
gi 1958660592 358 PERKFVFTCPTEKEQREWLESLRGVLS 384
Cdd:pfam00169  79 GKRTYLLQAESEEERKDWIKAIQSAIR 105

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  158 REGFLWKRGRDNSQFLRRRFVLLsREGLLKYYTKEE---GKTPKAIINIKDLNATFQTE--KIGHPHGLQITYRKEgqtR 232
Cdd:smart00233   3 KEGWLYKKSGGGKKSWKKRYFVL-FNSTLLYYKSKKdkkSYKPKGSIDLSGCTVREAPDpdSSKKPHCFEIKTSDR---K 78

                           90       100
                   ....*....|....*....|..
gi 1958660592  233 NLFVYHDSGKEIVDWFNALRAA 254
Cdd:smart00233  79 TLLLQAESEEEREKWVEALRKA 100

Arf1 GTPase-activating protein 2; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958660592  11 LLELLQAAGTgNGHCADCGAAgpacpctlvqslsssaeillfhpaDPDWASYKLGVFICLHCSGVHRNFP-DISKVKSVR 89
Cdd:cd09029     9 LFKRLRAIPT-NKACFDCGAK------------------------NPSWASITYGVFLCIDCSGVHRSLGvHLSFIRSTE 63

                          90       100
                  ....*....|....*....|....*
gi 1958660592  90 LDF-WDDSMVEFMTHNGNLSVKAKF 113
Cdd:cd09029    64 LDSnWNWFQLRCMQVGGNANATAFF 88

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.