Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLVVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 154
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 155 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 234
Cdd:cd04148   79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 157817444 235 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 295
Cdd:cd04148  159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLVVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 154
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 155 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 234
Cdd:cd04148   79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 157817444 235 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 295
Cdd:cd04148  159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444   76 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLVVDGEsatIILLDMWENKGENEW--LHDHCMQV 148
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  149 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 228
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 157817444  229 ELFEGIVRQVR 239
Cdd:pfam00071 151 EAFEELAREIL 161

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  76 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVLGEDTYERTLVVDGESATIILLDMwenKGENE----------WLHDHc 145
Cdd:COG1100    5 KIVVVGTGGVGKTSLVNRLVGDIFSLEKYLSTNGVTIDKKELKLDGLDVDLVIWDT---PGQDEfretrqfyarQLTGA- 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 146 mqvgDAYLIVYSITDRASFEKASELRIQLRRARqtEDIPIILVGNKSDLVRCREVsVSEGRACAVVFDCKF---IETSAA 222
Cdd:COG1100   81 ----SLYLFVVDGTREETLQSLYELLESLRRLG--KKSPIILVLNKIDLYDEEEI-EDEERLKEALSEDNIvevVATSAK 153

                        170       180
                 ....*....|....*....|....
gi 157817444 223 VQHNVKELFEGIVRQVRLRRDSKE 246
Cdd:COG1100  154 TGEGVEELFAALAEILRGEGDSLD 177

Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLVVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 154
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 155 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 234
Cdd:cd04148   79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 157817444 235 VRQVRLRRDSKEKNERRLAYQKRRESIPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 295
Cdd:cd04148  159 VRQVRLRRDSKEKNTRRMASRKRRESITKKAKRFLSKIVAKNNKGMAFKQKSKSCHDLSVL 219

Small GTPase of the Ras superfamily; ill-defined subfamily; SMART predicts Ras-like small GTPases of the ARF, RAB, RAN, RAS, and SAR subfamilies. Others that could not be classified in this way are predicted to be members of the small GTPase superfamily without predictions of the subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444    75 YRVVLIGEQGVGKSTL-----ANIFAGVHDSMDsdcevlgEDTYERTLVVDGESATIILLDmweNKGENEW--LHDHCMQ 147
Cdd:smart00010   3 YKLVVLGGGGVGKSALtiqfvQGHFVDEYDPTI-------EDSYRKQIEIDGEVCLLDILD---TAGQEEFsaMRDQYMR 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444   148 VGDAYLIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNV 227
Cdd:smart00010  73 TGEGFLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKERINV 152

                          170
                   ....*....|....
gi 157817444   228 KELFEGIVRQVRLR 241
Cdd:smart00010 153 DEAFYDLVREIRKS 166

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444   76 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLVVDGEsatIILLDMWENKGENEW--LHDHCMQV 148
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  149 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 228
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 157817444  229 ELFEGIVRQVR 239
Cdd:pfam00071 151 EAFEELAREIL 161

Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B; H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLVVDGESAtiiLLDMWENKGENEW--LHDHCMQVGDAY 152
Cdd:cd04138    2 YKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTI--EDSYRKQVVIDGETC---LLDILDTAGQEEYsaMRDQYMRTGEGF 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLvRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 232
Cdd:cd04138   77 LCVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDL-AARTVSTRQGQDLAKSYGIPYIETSAKTRQGVEEAFY 155

                 ....*..
gi 157817444 233 GIVRQVR 239
Cdd:cd04138  156 TLVREIR 162

Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases); The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  76 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLVVDGESATIILLDmweNKGENEW--LHDHCMQVGDAYL 153
Cdd:cd04144    1 KLVVLGDGGVGKTALTIQLCLNHFVETYDPTI--EDSYRKQVVVDGQPCMLEVLD---TAGQEEYtaLRDQWIREGEGFI 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 154 IVYSITDRASFEKASELRIQLRRARQTE--DIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELF 231
Cdd:cd04144   76 LVYSITSRSTFERVERFREQIQRVKDESaaDVPIMIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNVNVERAF 155

                        170
                 ....*....|.
gi 157817444 232 EGIVRQVRLRR 242
Cdd:cd04144  156 YTLVRALRQQR 166

Ral (Ras-like) family containing highly homologous RalA and RalB; The Ral (Ras-like) subfamily consists of the highly homologous RalA and RalB. Ral proteins are believed to play a crucial role in tumorigenesis, metastasis, endocytosis, and actin cytoskeleton dynamics. Despite their high sequence similarity (>80% sequence identity), nonoverlapping and opposing functions have been assigned to RalA and RalBs in tumor migration. In human bladder and prostate cancer cells, RalB promotes migration while RalA inhibits it. A Ral-specific set of GEFs has been identified that are activated by Ras binding. This RalGEF activity is enhanced by Ras binding to another of its target proteins, phosphatidylinositol 3-kinase (PI3K). Ral effectors include RLIP76/RalBP1, a Rac/cdc42 GAP, and the exocyst (Sec6/8) complex, a heterooctomeric protein complex that is involved in tethering vesicles to specific sites on the plasma membrane prior to exocytosis. In rat kidney cells, RalB is required for functional assembly of the exocyst and for localizing the exocyst to the leading edge of migrating cells. In human cancer cells, RalA is required to support anchorage-independent proliferation and RalB is required to suppress apoptosis. RalA has been shown to localize to the plasma membrane while RalB is localized to the intracellular vesicles. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLVVDGESatiILLDMWENKGENEW--LHDHCMQVGDAY 152
Cdd:cd04139    1 HKVIMVGSGGVGKSALTLQF--MYDEFVEDYEPTKADSYRKKVVLDGEE---VQLNILDTAGQEDYaaIRDNYFRSGEGF 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 232
Cdd:cd04139   76 LLVFSITDMESFTALAEFREQILRVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFF 155

                 ....*..
gi 157817444 233 GIVRQVR 239
Cdd:cd04139  156 DLVREIR 162

Rap2 family GTPase consists of Rap2a, Rap2b, and Rap2c; The Rap2 subgroup is part of the Rap subfamily of the Ras family. It consists of Rap2a, Rap2b, and Rap2c. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLVVDGESATIILLDmweNKGENEW--LHDHCMQVGDAY 152
Cdd:cd04176    2 YKVVVLGSGGVGKSALTVQF--VSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILD---TAGTEQFasMRDLYIKNGQGF 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 232
Cdd:cd04176   77 IVVYSLVNQQTFQDIKPMRDQIVRVKGYEKVPIILVGNKVDLESEREVSSAEGRALAEEWGCPFMETSAKSKTMVNELFA 156

                 ....*.
gi 157817444 233 GIVRQV 238
Cdd:cd04176  157 EIVRQM 162

Ras-related in brain (Rab) family of small guanosine triphosphatases (GTPases); Rab GTPases form the largest family within the Ras superfamily. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. Rab GTPases are small, monomeric proteins that function as molecular switches to regulate vesicle trafficking pathways. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they regulate distinct steps in membrane traffic pathways. In the GTP-bound form, Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which mask C-terminal lipid binding and promote cytosolic localization. While most unicellular organisms possess 5-20 Rab members, several have been found to possess 60 or more Rabs; for many of these Rab isoforms, homologous proteins are not found in other organisms. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Since crystal structures often lack C-terminal residues, the lipid modification site is not available for annotation in many of the CDs in the hierarchy, but is included where possible.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEV-LGEDTYERTLVVDGESatiILLDMWenkgenewlhDHCMQ-----V 148
Cdd:cd00154    1 FKIVLIGDSGVGKTSLLLRF--VDNKFSENYKStIGVDFKSKTIEVDGKK---VKLQIW----------DTAGQerfrsI 65

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 149 GDAY-------LIVYSITDRASFEKASELRIQLRRaRQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSA 221
Cdd:cd00154   66 TSSYyrgahgaILVYDVTNRESFENLDKWLNELKE-YAPPNIPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSA 144

                        170
                 ....*....|....*
gi 157817444 222 AVQHNVKELFEGIVR 236
Cdd:cd00154  145 KTGENVDEAFESLAR 159

Rab subfamily of small GTPases; Rab GTPases are implicated in vesicle trafficking.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444    75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEV-LGEDTYERTLVVDGesaTIILLDMWENKGenewlhdhcmQ-----V 148
Cdd:smart00175   1 FKIILIGDSGVGKSSLLSRF--TDGKFSEQYKStIGVDFKTKTIEVDG---KRVKLQIWDTAG----------QerfrsI 65

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444   149 GDAY-------LIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSA 221
Cdd:smart00175  66 TSSYyrgavgaLLVYDITNRESFENLENWLKELREYAS-PNVVIMLVGNKSDLEEQRQVSREEAEAFAEEHGLPFFETSA 144

                          170
                   ....*....|....*..
gi 157817444   222 AVQHNVKELFEGIVRQV 238
Cdd:smart00175 145 KTNTNVEEAFEELAREI 161

A Ras homolog member I (ARHI); ARHI (A Ras homolog member I) is a member of the Ras family with several unique structural and functional properties. ARHI is expressed in normal human ovarian and breast tissue, but its expression is decreased or eliminated in breast and ovarian cancer. ARHI contains an N-terminal extension of 34 residues (human) that is required to retain its tumor suppressive activity. Unlike most other Ras family members, ARHI is maintained in the constitutively active (GTP-bound) state in resting cells and has modest GTPase activity. ARHI inhibits STAT3 (signal transducers and activators of transcription 3), a latent transcription factor whose abnormal activation plays a critical role in oncogenesis. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLvvdGESATIILLDMWENKGENEW--LHDHCMQVGDAY 152
Cdd:cd04140    2 YRVVVFGAGGVGKSSLVLRF--VKGTFRESYIPTIEDTYRQVI---SCSKSICTLQITDTTGSHQFpaMQRLSISKGHAF 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 LIVYSITDRASFEKASELRIQLRRAR--QTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKEL 230
Cdd:cd04140   77 ILVYSITSKQSLEELKPIYELICEIKgnNLEKIPIMLVGNKCDESPSREVSSSEGAALARTWNCAFMETSAKTNHNVQEL 156

                 ..
gi 157817444 231 FE 232
Cdd:cd04140  157 FQ 158

Rab GTPase family 21 (Rab21); The localization and function of Rab21 are not clearly defined, with conflicting data reported. Rab21 has been reported to localize in the ER in human intestinal epithelial cells, with partial colocalization with alpha-glucosidase, a late endosomal/lysosomal marker. More recently, Rab21 was shown to colocalize with and affect the morphology of early endosomes. In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDT-YERTLVVDGESATiilLDMWENKGENEWlhdHCM-----QV 148
Cdd:cd04123    1 FKVVLLGEGRVGKTSLVLRY--VENKFNEKHESTTQASfFQKTVNIGGKRID---LAIWDTAGQERY---HALgpiyyRD 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 149 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 228
Cdd:cd04123   73 ADGAILVYDITDADSFQKVKKWIKELKQMRG-NNISLVIVGNKIDLERQRVVSKSEAEEYAKSVGAKHFETSAKTGKGIE 151

                        170
                 ....*....|
gi 157817444 229 ELFEGIVRQV 238
Cdd:cd04123  152 ELFLSLAKRM 161

Rab GTPase family 6 (Rab6); Rab6 is involved in microtubule-dependent transport pathways through the Golgi and from endosomes to the Golgi. Rab6A of mammals is implicated in retrograde transport through the Golgi stack, and is also required for a slow, COPI-independent, retrograde transport pathway from the Golgi to the endoplasmic reticulum (ER). This pathway may allow Golgi residents to be recycled through the ER for scrutiny by ER quality-control systems. Yeast Ypt6p, the homolog of the mammalian Rab6 GTPase, is not essential for cell viability. Ypt6p acts in endosome-to-Golgi, in intra-Golgi retrograde transport, and possibly also in Golgi-to-ER trafficking. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFagVHDSMDsdcevlgeDTYERTLVVDGESATI------ILLDMWENKGEnEWLH------ 142
Cdd:cd01861    1 HKLVFLGDQSVGKTSIITRF--MYDTFD--------NQYQATIGIDFLSKTMyvddktVRLQLWDTAGQ-ERFRslipsy 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 143 --DHCMQVgdaylIVYSITDRASFEKASELrIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETS 220
Cdd:cd01861   70 irDSSVAV-----VVYDITNRQSFDNTDKW-IDDVRDERGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETS 143

                        170
                 ....*....|....
gi 157817444 221 AAVQHNVKELFEGI 234
Cdd:cd01861  144 AKAGHNVKQLFKKI 157

Rab GTPase family 11 (Rab11)-like includes Rab11a, Rab11b, and Rab25; Rab11a, Rab11b, and Rab25 are closely related, evolutionary conserved Rab proteins that are differentially expressed. Rab11a is ubiquitously synthesized, Rab11b is enriched in brain and heart and Rab25 is only found in epithelia. Rab11/25 proteins seem to regulate recycling pathways from endosomes to the plasma membrane and to the trans-Golgi network. Furthermore, Rab11a is thought to function in the histamine-induced fusion of tubulovesicles containing H+, K+ ATPase with the plasma membrane in gastric parietal cells and in insulin-stimulated insertion of GLUT4 in the plasma membrane of cardiomyocytes. Overexpression of Rab25 has recently been observed in ovarian cancer and breast cancer, and has been correlated with worsened outcomes in both diseases. In addition, Rab25 overexpression has also been observed in prostate cancer, transitional cell carcinoma of the bladder, and invasive breast tumor cells. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlGEDTYERTLVVDGEsatIILLDMWENKGENEWLhdhcmQVGDAY-- 152
Cdd:cd01868    4 FKIVLIGDSGVGKSNLLSRFTRNEFNLDSKSTI-GVEFATRTIQIDGK---TIKAQIWDTAGQERYR-----AITSAYyr 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 -----LIVYSITDRASFEKA----SELRiqlrrARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAV 223
Cdd:cd01868   75 gavgaLLVYDITKKSTFENVerwlKELR-----DHADSNIVIMLVGNKSDLRHLRAVPTEEAKAFAEKNGLSFIETSALD 149

                        170
                 ....*....|....*
gi 157817444 224 QHNVKELFEGIVRQV 238
Cdd:cd01868  150 GTNVEEAFKQLLTEI 164

Rab GTPase family 39 (Rab39); Found in eukaryotes, Rab39 is mainly found in epithelial cell lines, but is distributed widely in various human tissues and cell lines. It is believed to be a novel Rab protein involved in regulating Golgi-associated vesicular transport during cellular endocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLAN-----IFAGVHDSmdsdceVLGEDTYERTlvVDGESATIILLDMWENKGENEWlhdhcMQVG 149
Cdd:cd04111    3 FRLIVIGDSTVGKSSLLKrftegRFAEVSDP------TVGVDFFSRL--IEIEPGVRIKLQLWDTAGQERF-----RSIT 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 150 DAY-------LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAA 222
Cdd:cd04111   70 RSYyrnsvgvLLVFDITNRESFEHVHDWLEEARSHIQPHRPVFILVGHKCDLESQRQVTREEAEKLAKDLGMKYIETSAR 149

                        170       180
                 ....*....|....*....|....
gi 157817444 223 VQHNVKELFEGIVRQVRLRRDSKE 246
Cdd:cd04111  150 TGDNVEEAFELLTQEIYERIKRGE 173

Rab GTPase families 8, 10, 13 (Rab8, Rab10, Rab13); Rab8/Sec4/Ypt2 are known or suspected to be involved in post-Golgi transport to the plasma membrane. It is likely that these Rabs have functions that are specific to the mammalian lineage and have no orthologs in plants. Rab8 modulates polarized membrane transport through reorganization of actin and microtubules, induces the formation of new surface extensions, and has an important role in directed membrane transport to cell surfaces. The Ypt2 gene of the fission yeast Schizosaccharomyces pombe encodes a member of the Ypt/Rab family of small GTP-binding proteins, related in sequence to Sec4p of Saccharomyces cerevisiae but closer to mammalian Rab8. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLanIFAGVHDSM-DSDCEVLGEDTYERTLVVDGESatiILLDMWENKGEnEWLHdhcmQVGDAY- 152
Cdd:cd01867    4 FKLLLIGDSGVGKSCL--LLRFSEDSFnPSFISTIGIDFKIRTIELDGKK---IKLQIWDTAGQ-ERFR----TITTSYy 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 ------LIVYSITDRASFEkasELRIQLRRARQ--TEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQ 224
Cdd:cd01867   74 rgamgiILVYDITDEKSFE---NIKNWMRNIDEhaSEDVERMLVGNKCDMEEKRVVSKEEGEALAREYGIKFLETSAKAN 150

                        170
                 ....*....|....*..
gi 157817444 225 HNVKELFEGIVRQVRLR 241
Cdd:cd01867  151 INVEEAFLTLAKDILKK 167

Rab GTPase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444  75 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDcEVLGEDTYERTLVVDGESatiILLDMWENKGENEWlhdhcMQVGDAY-- 152
Cdd:PLN03110  13 FKIVLIGDSGVGKSNILSRFTRNEFCLESK-STIGVEFATRTLQVEGKT---VKAQIWDTAGQERY-----RAITSAYyr 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157817444 153 -----LIVYSITDRASFEKASELriqLRRARQTED--IPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQH 225
Cdd:PLN03110  84 gavgaLLVYDITKRQTFDNVQRW---LRELRDHADsnIVIMMAGNKSDLNHLRSVAEEDGQALAEKEGLSFLETSALEAT 160