Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain; APPL interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663 482 FPEAEDSLLQQMFIVRFLGSMAVKTDSTTEVIYEAMRQVLAARAIHNIFRMTESHLMVTSQSLRLIDPQTQVSRANFELT 561
Cdd:cd13158   1 SSEDEDSLLQQLFIVRFLGSMEVKSDRTSEVIYEAMRQVLAARAIHNIFRMTESHLLVTSDCLRLIDPQTQVTRARFPLA 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 24586663 562 SVTQFAAHQENKRLVGFVIRVPESTGEE-SLSTYIFESNSEGEKICYAINLGKEI 615
Cdd:cd13158  81 DVVQFAAHQENKRLFGFVVRTPEGDGEEpSFSCYVFESNTEGEKICDAIALAKQI 135

BAR domain of APPL family; BAR_12 is the BAR coiled-coil domain at the N-terminus of APPL or adaptor protein containing PH domain, PTB domain, and leucine zipper motif proteins in higher eukaryotes. This BAR domain contains four helices whereas the other classical BAR domains contain only three helices. The first three helices form an antiparallel coiled-coil, while the fourth helix, is unique to APPL1. BAR domains take part in many varied biological processes such as fission of synaptic vesicles, endocytosis, regulation of the actin cytoskeleton, transcriptional repression, cell-cell fusion, apoptosis, secretory vesicle fusion, and tissue differentiation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663     7 LLLEEALQDSPQTRSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNfalgKGDEEVISTL 86
Cdd:pfam16746   1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEF----IGDEETDESL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663    87 HYFSKVVDELNLLHTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKtEVGKE 166
Cdd:pfam16746  77 KKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELE-EADNE 155

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663   167 VAAARRKQHLSSLQYYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEMFsKRMDSFLSSVADMVQSIQVELEAEAEK 246
Cdd:pfam16746 156 LAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELF-KDLEPFMKDLQAQLQQTREDTREEKEE 234

                  .
gi 24586663   247 M 247
Cdd:pfam16746 235 L 235

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain; APPL (also called DCC-interacting protein (DIP)-13alpha) interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. 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 24586663 252 QELLSVDESVYTPDSDVAAPQINRNLIQKAGYLNLRNKTGLVTTTWERLYFFTQGGNLMCQPRGAVAGGLIQDLDNCSVM 331
Cdd:cd13247   1 EELSSSADYFYEGDPDETQAAPNRNLTQKAGYLFIRSKTGLVTNKWDRTYFFTQGGNLMSQPRDEVAGSLVLDLDNCSVQ 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 24586663 332 AVDCEDRRYCFQITTPNGKSGIILQAESRKENEEWICAINNISRQ 376
Cdd:cd13247  81 AADCEDRRNVFQITSPDGKKAIVLQAESKKDYEEWIATINNISQQ 125

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 24586663    278 IQKAGYLNLRNKTGLvtTTWERLYFFTQGGNLMC-----QPRGAVAGGLIqDLDNCSVMAVDCED---RRYCFQITTPNG 349
Cdd:smart00233   1 VIKEGWLYKKSGGGK--KSWKKRYFVLFNSTLLYykskkDKKSYKPKGSI-DLSGCTVREAPDPDsskKPHCFEIKTSDR 77

                           90       100
                   ....*....|....*....|....*.
gi 24586663    350 KSgIILQAESRKENEEWICAINNISR 375
Cdd:smart00233  78 KT-LLLQAESEEEREKWVEALRKAIA 102

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663   494 FIVRFLGSMAVKTDST------TEVIYEAMRQVLAA------RAIHNIFRMTESHLMVTSQSLRLIDPQTQVSRANFELT 561
Cdd:pfam00640   1 FAVRYLGSVEVPEERApdkntrMQQAREAIRRVKAAkinkirGLSGETGPGTKVDLFISTDGLKLLNPDTQELIHDHPLV 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 24586663   562 SVTqFAAHQE--NKRLVGFVIRVPEStgeESLSTYIFESNSEGEKICYAI 609
Cdd:pfam00640  81 SIS-FCADGDpdLMRYFAYIARDKAT---NKFACHVFESEDGAQDIAQSI 126

The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing (APPL) proteins are effectors of the small GTPase Rab5 that function in endosome-mediated signaling. They contain BAR, pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. They form homo- and hetero-oligomers that are mediated by their BAR domains, and are localized to cytoplasmic membranes. Vertebrates contain two APPL proteins, APPL1 and APPL2. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  20 RSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNFALGKGDEEVISTLHYFSKVVDELNLL 99
Cdd:cd07601   1 RSLLNVFEEDALQLSSYMNQLLQACKRVYDAQNELKSATQALSKKLGEYEKQKFELGRDDEILVSTLKQFSKVVDELSTM 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663 100 HTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKTEVGKEVAAARRKQHLSSL 179
Cdd:cd07601  81 HSTLSSQLADTVLHPISQFMESDLAEIMTLKELFKAASNDHDGVLSKYSRLSKKRENTKVKIEVNDEVYACRKKQHQTAM 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*
gi 24586663 180 QYYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEMFSKRMDSFLSSVADMVQ 234
Cdd:cd07601 161 NYYCALNLLQYKKTTALLEPMIGYLQAQIAFFKMGPEMFTRQTEEFLSDINTSVQ 215

The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing 1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing (APPL) proteins are effectors of the small GTPase Rab5 that function in endosome-mediated signaling. They contain BAR, pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. They form homo- and hetero-oligomers that are mediated by their BAR domains. Vertebrates contain two APPL proteins, APPL1 and APPL2. APPL1 interacts with diverse receptors (e.g. NGF receptor TrkA, FSHR, adiponectin receptors) and signaling proteins (e.g. Akt, PI3K), and may function as an adaptor linked to many distinct signaling pathways. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  20 RSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNFALGKGDEEVISTLHYFSKVVDELNLL 99
Cdd:cd07631   1 RSLLGVFEEDAAAISNYFNQLFQAMHRIYDAQNELSAATHLTSKLLKEYEKQRFPLGGDDEVMSSTLQQFSKVIDELSSC 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663 100 HTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKTEVGKEVAAARRKQHLSSL 179
Cdd:cd07631  81 HAVLSTQLADAMMFPITQFKERDLKEILTLKEVFQIASNDHDAAINRYSRLSKRRENEKVKYEVTEDVYTSRKKQHQTMM 160

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*
gi 24586663 180 QYYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEMFSKRMDSFLSSVADMVQ 234
Cdd:cd07631 161 HYFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLNEQLEEFLTNIGTSVQ 215

Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain; APPL (also called DCC-interacting protein (DIP)-13alpha) interacts with oncoprotein serine/threonine kinase AKT2, tumor suppressor protein DCC (deleted in colorectal cancer), Rab5, GIPC (GAIP-interacting protein, C terminus), human follicle-stimulating hormone receptor (FSHR), and the adiponectin receptors AdipoR1 and AdipoR2. There are two isoforms of human APPL: APPL1 and APPL2, which share about 50% sequence identity. APPL has a BAR and a PH domain near its N terminus, and the two domains are thought to function as a unit (BAR-PH domain). C-terminal to this is a PTB domain. Lipid binding assays show that the BAR, PH, and PTB domains can bind phospholipids. 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 24586663 252 QELLSVDESVYTPDSDVAAPQINRNLIQKAGYLNLRNKTGLVTTTWERLYFFTQGGNLMCQPRGAVAGGLIQDLDNCSVM 331
Cdd:cd13247   1 EELSSSADYFYEGDPDETQAAPNRNLTQKAGYLFIRSKTGLVTNKWDRTYFFTQGGNLMSQPRDEVAGSLVLDLDNCSVQ 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 24586663 332 AVDCEDRRYCFQITTPNGKSGIILQAESRKENEEWICAINNISRQ 376
Cdd:cd13247  81 AADCEDRRNVFQITSPDGKKAIVLQAESKKDYEEWIATINNISQQ 125

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. 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 24586663 280 KAGYLNLRNKTGLvtTTWERLYFFTQGGNLMCQPRG-----AVaggLIQDLDNCSVMAVDCEDRRYCFQITTPNgKSgII 354
Cdd:cd13250   1 KEGYLFKRSSNAF--KTWKRRWFSLQNGQLYYQKRDkkdepTV---MVEDLRLCTVKPTEDSDRRFCFEVISPT-KS-YM 73

                        90       100
                ....*....|....*....|...
gi 24586663 355 LQAESRKENEEWICAINN-ISRQ 376
Cdd:cd13250  74 LQAESEEDRQAWIQAIQSaIASA 96

Snf1p-interacting protein 3 Pleckstrin homology (PH) domain; SIP3 interacts with SNF1 protein kinase and activates transcription when anchored to DNA. It may function in the SNF1 pathway. SIP3 contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain followed by a PH domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. 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 24586663 279 QKAGYLNLRNKTGLVT-TTWERLYFFTQG---GNLMCQPrgavAGGLIQDLD-----NCSVMAVDCEDRRYCFQITTPNG 349
Cdd:cd13280   1 EKSGWLYMKTSVGKPNrTIWVRRWCFVKNgvfGMLSLSP----SKTYVEETDkfgvlLCSVRYAPEEDRRFCFEVKIFKD 76

                        90       100       110
                ....*....|....*....|....*....|
gi 24586663 350 KSgIILQAESRKENEEWICAINNiSRQIYL 379
Cdd:cd13280  77 IS-IILQAETLKELKSWLTVFEN-AKRYAL 104

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663 494 FIVRFLGSMAVKTDSTTEVIYEAMRQVLAARAiHNIFRMTESHLMVTSQSLRLIDPQTQVSRANFELTSVTQFAAHQENK 573
Cdd:cd00934   3 FQVKYLGSVEVGSSRGVDVVEEALKALAAALK-SSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDPDNP 81

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 24586663 574 RLVGFVIRVPESTGEESlstYIFESNS--EGEKICYAI 609
Cdd:cd00934  82 NVFAFIAGEEGGSGFRC---HVFQCEDeeEAEEILQAI 116

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 24586663    278 IQKAGYLNLRNKTGLvtTTWERLYFFTQGGNLMC-----QPRGAVAGGLIqDLDNCSVMAVDCED---RRYCFQITTPNG 349
Cdd:smart00233   1 VIKEGWLYKKSGGGK--KSWKKRYFVLFNSTLLYykskkDKKSYKPKGSI-DLSGCTVREAPDPDsskKPHCFEIKTSDR 77

                           90       100
                   ....*....|....*....|....*.
gi 24586663    350 KSgIILQAESRKENEEWICAINNISR 375
Cdd:smart00233  78 KT-LLLQAESEEEREKWVEALRKAIA 102

The Bin/Amphiphysin/Rvs (BAR) domain of Rho GTPase activating protein 10-like; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This group is composed of uncharacterized proteins called Rho GTPase activating protein (GAP) 10-like. GAP10-like may be a GAP with activity towards RhoA and Cdc42. Similar to GRAF and GRAF2, it contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of the related proteins GRAF and OPHN1, directly interact with their Rho GAP domains and inhibit theiractivity. The autoinhibited proteins are capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  36 YTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNFALGKGDEEV--ISTLHYFSKVVDELNLLHTELAKQLADTMVL 113
Cdd:cd07634  17 FIKELIKDGSLLIGALRNLSMAVQKFSQSLQDFQFECIGDAETDDEIsiAQSLKEFARLLIAVEEERRRLIQNANDVLIA 96

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663 114 PIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKTEVgKEVAAARRKQHLSSLQYYCALNALQYRKQ 193
Cdd:cd07634  97 PLEKFRKEQIGAAKDGKKKFDKESEKYYSILEKHLNLSAKKKESHLQRAD-TQIDREHQNFYEASLEYVFKIQEVQEKKK 175

                       170       180
                ....*....|....*....|....
gi 24586663 194 MAMMEPMIGFAHGQINFFKKGAEM 217
Cdd:cd07634 176 FEFVEPLLAFLQGLFTFYHEGYEL 199

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663   278 IQKAGYLnlRNKTGLVTTTWERLYFFTQGGNL-MCQPRGAVAGGLIQ---DLDNCSVMAVDCED---RRYCFQITTP--N 348
Cdd:pfam00169   1 VVKEGWL--LKKGGGKKKSWKKRYFVLFDGSLlYYKDDKSGKSKEPKgsiSLSGCEVVEVVASDspkRKFCFELRTGerT 78

                          90       100
                  ....*....|....*....|....*..
gi 24586663   349 GKSGIILQAESRKENEEWICAINNISR 375
Cdd:pfam00169  79 GKRTYLLQAESEEERKDWIKAIQSAIR 105

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion kinase; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. GTPase Regulator Associated with Focal adhesion kinase (GRAF), also called Rho GTPase activating protein 26 (ARHGAP26), is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domain of GRAF directly interacts with its Rho GAP domain and inhibits its activity. Autoinhibited GRAF is capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  20 RSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNFALGKGDEE--VISTLHYFSKVVDELN 97
Cdd:cd07636   1 RERLKSHEAELDKTNKFIKELIKDGKSLIAALKNLSSAKRKFADSLNEFKFQCIGDAETDDEicIARSLQEFAAVLRNLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  98 LLHTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKtEVGKEVAAARRKQHLS 177
Cdd:cd07636  81 DERTRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCAVLEKHLNLSSKKKESQLH-EADSQVDLVRQHFYEV 159

                       170       180       190       200
                ....*....|....*....|....*....|....*....|
gi 24586663 178 SLQYYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEM 217
Cdd:cd07636 160 SLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYEL 199

GTPase Regulator Associated with Focal adhesion and related proteins Pleckstrin homology (PH) domain; This hierarchy contains GRAF family members: OPHN1/oligophrenin1, GRAF1 (also called ARHGAP26/Rho GTPase activating protein 26), GRAF2 (also called ARHGAP10/ARHGAP42), AK057372, and LOC129897, all of which are members of the APPL family. OPHN1 is a RhoGAP involved in X-linked mental retardation, epilepsy, rostral ventricular enlargement, and cerebellar hypoplasia. Affected individuals have morphological abnormalities of their brain with enlargement of the cerebral ventricles and cerebellar hypoplasia. OPHN1 negatively regulates RhoA, Cdc42, and Rac1 in neuronal and non-neuronal cells. GRAF1 sculpts the endocytic membranes of the CLIC/GEEC (clathrin-independent carriers/GPI-enriched early endosomal compartments) endocytic pathway. It strongly interacts with dynamin and inhibition of dynamin abolishes CLIC/GEEC endocytosis. GRAF2, GRAF3 and oligophrenin are likely to play similar roles during clathrin-independent endocytic events. GRAF1 mutations are linked to leukaemia. All members are composed of a N-terminal BAR-PH domain, followed by a RhoGAP domain, a proline rich region, and a C-terminal SH3 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 24586663 280 KAGYLNLRNKTGLvTTTWERLY-FFTQGGNLM------CQPRGAVAGGLIQDLDNCSVMAVDCEDRRYCFQITTPNGKSG 352
Cdd:cd01249   2 KEGYLYLQEKKPL-GSTWTKHYcTYRKESKMFtmipynQQSSGKLGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                        90
                ....*....|....*...
gi 24586663 353 IILQAESRKENEEWICAI 370
Cdd:cd01249  81 LTLQALSEEDRKLWLEAM 98

The Bin/Amphiphysin/Rvs (BAR) domain of ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of ACAPs (ArfGAP with Coiled-coil, ANK repeat and PH domain containing proteins), which are Arf GTPase activating proteins (GAPs) containing an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, and C-terminal ankyrin (ANK) repeats. Vertebrates contain at least three members, ACAP1, ACAP2, and ACAP3. ACAP1 and ACAP2 are Arf6-specific GAPs, involved in the regulation of endocytosis, phagocytosis, cell adhesion and migration, by mediating Arf6 signaling. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  74 ALGKGDEEVISTLHYFSKVVDELNLLHTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKK 153
Cdd:cd07603  51 DYFRDDSLVQNCLNKFIQALQEMNNFHTILLDQAQRTVSTQLQNFVKEDIKKVKESKKHFEKISDDLDNALVKNAQAPRS 130

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24586663 154 KENEkvkTEVGKEVAAARRK--QHLsSLQYYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEMFSK 220
Cdd:cd07603 131 KPQE---AEEATNILTATRScfRHT-ALDYVLQINVLQAKKRHEILSTLLSYMHAQFTFFHQGYDLLED 195

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 24586663 280 KAGYLNlrnKTGLVTTTWERLYFFTQGGNLMC---------QPRGAVAggliqdLDN-CSVMavdCEDRRYCFQITTPng 349
Cdd:cd13282   1 KAGYLT---KLGGKVKTWKRRWFVLKNGELFYykspndvirKPQGQIA------LDGsCEIA---RAEGAQTFEIVTE-- 66

                        90       100
                ....*....|....*....|....*.
gi 24586663 350 KSGIILQAESRKENEEWICAINNISR 375
Cdd:cd13282  67 KRTYYLTADSENDLDEWIRVIQNVLR 92

Type 2 Diacylglycerol kinase Pleckstrin homology (PH) domain; DGK (also called DAGK) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) utilizing ATP as a source of the phosphate. In non-stimulated cells, DGK activity is low and DAG is used for glycerophospholipid biosynthesis. Upon receptor activation of the phosphoinositide pathway, DGK activity increases which drives the conversion of DAG to PA. DGK acts as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another. There are 9 mammalian DGK isoforms all with conserved catalytic domains and two cysteine rich domains. These are further classified into 5 groups according to the presence of additional functional domains and substrate specificity: Type 1 - DGK-alpha, DGK-beta, DGK-gamma - contain EF-hand motifs and a recoverin homology domain; Type 2 - DGK-delta, DGK-eta, and DGK-kappa- contain a pleckstrin homology domain, two cysteine-rich zinc finger-like structures, and a separated catalytic region; Type 3 - DGK-epsilon - has specificity for arachidonate-containing DAG; Type 4 - DGK-zeta, DGK-iota- contain a MARCKS homology domain, ankyrin repeats, a C-terminal nuclear localization signal, and a PDZ-binding motif; Type 5 - DGK-theta - contains a third cysteine-rich domain, a pleckstrin homology domain and a proline rich region. The type 2 DGKs are present as part of this Metazoan DGK hierarchy. They have a N-terminal PH domain, two cysteine rich domains, followed by bipartite catalytic domains, and a C-terminal SAM domain. Their catalytic domains and perhaps other DGK catalytic domains may function as two independent units in a coordinated fashion. They may also require other motifs for maximal activity because several DGK catalytic domains have very little DAG kinase activity when expressed as isolated subunits. 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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 24586663 324 DLDNCSVMAVDCEDRRYCFQITTPNGKsgIILQAESRKENEEWICAINNIS-RQIY 378
Cdd:cd13274  43 DLSDASVAECSTKNVNNSFTVITPFRK--LILCAESRKEMEEWISALKTVQqREFY 96

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663   494 FIVRFLGSMAVKTDST------TEVIYEAMRQVLAA------RAIHNIFRMTESHLMVTSQSLRLIDPQTQVSRANFELT 561
Cdd:pfam00640   1 FAVRYLGSVEVPEERApdkntrMQQAREAIRRVKAAkinkirGLSGETGPGTKVDLFISTDGLKLLNPDTQELIHDHPLV 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 24586663   562 SVTqFAAHQE--NKRLVGFVIRVPEStgeESLSTYIFESNSEGEKICYAI 609
Cdd:pfam00640  81 SIS-FCADGDpdLMRYFAYIARDKAT---NKFACHVFESEDGAQDIAQSI 126

The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin-1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Oligophrenin-1 (OPHN1) is a GTPase activating protein (GAP) with activity towards RhoA, Rac, and Cdc42, that is expressed in developing spinal cord and in adult brain areas with high plasticity. It plays a role in regulating the actin cystoskeleton as well as morphology changes in axons and dendrites, and may also function in modulating neuronal connectivity. Mutations in the OPHN1 gene causes X-linked mental retardation associated with cerebellar hypoplasia, lateral ventricle enlargement and epilepsy. OPHN1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  20 RSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQLSKQLLAYEKQNFALGKGDEE--VISTLHYFSKVVDELN 97
Cdd:cd07633   1 RERLKCYEQELERTNKFIKDVIKDGNALISAIKEYSSAVQKFSQTLQSFQFDFIGDTLTDDEinIAESFKEFAELLQEVE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586663  98 LLHTELAKQLADTMVLPIIQFREKDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKtEVGKEVAAARRKQHLS 177
Cdd:cd07633  81 EERMMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDSEKFYSLLDRHVNLSSKKKESQLQ-EADLQVDKERQNFYES 159

                       170       180
                ....*....|....*....|....*...
gi 24586663 178 SLQYYCALNALQYRKQMAMMEPMIGFAH 205
Cdd:cd07633 160 SLEYVYQIQEVQESKKFDVVEPVLAFLH 187

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. 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 24586663 273 INRNLIQKAGYLNlrnKTGLVTTTWERLYFFTQGGNLMCQpRGAVAGGLIQDLDNCSVMAV-DCEDRRY--CFQITTPNg 349
Cdd:cd13255   1 MISEAVLKAGYLE---KKGERRKTWKKRWFVLRPTKLAYY-KNDKEYRLLRLIDLTDIHTCtEVQLKKHdnTFGIVTPA- 75

                        90       100       110
                ....*....|....*....|....*....|....
gi 24586663 350 kSGIILQAESRKENEEWICAINNIsRQIYLTDNP 383
Cdd:cd13255  76 -RTFYVQADSKAEMESWISAINLA-RQALRATIT 107

Dedicator of cytokinesis-D subfamily Pleckstrin homology (PH) domain; DOCK-D subfamily (also called Zizimin subfamily) consists of Dock9/Zizimin1, Dock10/Zizimin3, and Dock11/Zizimin2. DOCK-D has a N-terminal DUF3398 domain, a PH-like domain, a Dock Homology Region 1, DHR1 (also called CZH1), a C2 domain, and a C-terminal DHR2 domain (also called CZH2). Zizimin1 is enriched in the brain, lung, and kidney; zizimin2 is found in B and T lymphocytes, and zizimin3 is enriched in brain, lung, spleen and thymus. Zizimin1 functions in autoinhibition and membrane targeting. Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. No function has been determined for Zizimin3 to date. The N-terminal half of zizimin1 binds to the GEF domain through three distinct areas, including CZH1, to inhibit the interaction with Cdc42. In addition its PH domain binds phosphoinositides and mediates zizimin1 membrane targeting. DOCK is a family of proteins involved in intracellular signalling networks. They act as guanine nucleotide exchange factors for small G proteins of the Rho family, such as Rac and Cdc42. There are 4 subfamilies of DOCK family proteins based on their sequence homology: A-D. 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
                ....*....|....*....|....*....|....*....|....*....
gi 24586663 325 LDNCSVMAVDCEDRRYCFQITTpNGKSGIILQAESRKENEEWICAINNI 373
Cdd:cd13267  65 LDSCTGVVQNSKRRKFCFELRM-QDKKSYVLAAESEAEMDEWISKLNKI 112