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 4885263   76 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLMVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 155
Cdd:cd04148   1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  156 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 235
Cdd:cd04148  79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4885263  236 VRQVRLRRDSKEKNERRLAYQKRKESMPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 296
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 4885263   76 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLMVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 155
Cdd:cd04148   1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  156 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 235
Cdd:cd04148  79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4885263  236 VRQVRLRRDSKEKNERRLAYQKRKESMPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 296
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 4885263     77 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLMVDGEsatIILLDMWENKGENEW--LHDHCMQV 149
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263    150 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 229
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 4885263    230 ELFEGIVRQVR 240
Cdd:pfam00071 151 EAFEELAREIL 161

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263   77 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVLGEDTYERTLMVDGESATIILLDMwenKGENE----------WLHDHc 146
Cdd:COG1100   5 KIVVVGTGGVGKTSLVNRLVGDIFSLEKYLSTNGVTIDKKELKLDGLDVDLVIWDT---PGQDEfretrqfyarQLTGA- 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  147 mqvgDAYLIVYSITDRASFEKASELRIQLRRARqtEDIPIILVGNKSDLVRCREVsVSEGRACAVVFDCKF---IETSAA 223
Cdd:COG1100  81 ----SLYLFVVDGTREETLQSLYELLESLRRLG--KKSPIILVLNKIDLYDEEEI-EDEERLKEALSEDNIvevVATSAK 153

                       170       180
                ....*....|....*....|....
gi 4885263  224 VQHNVKELFEGIVRQVRLRRDSKE 247
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 4885263   76 YRVVLIGEQGVGKSTLANIFAGvHDSMDSDCEVLGEDTYERTLMVDGESATIILLDMWENKGeNEWLHDHCMQVGDAYLI 155
Cdd:cd04148   1 YRVVLLGDSGVGKSSLANIFTA-GVYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYVI 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  156 VYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFEGI 235
Cdd:cd04148  79 VYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGI 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4885263  236 VRQVRLRRDSKEKNERRLAYQKRKESMPRKARRFWGKIVAKNNKNMAFKLKSKSCHDLSVL 296
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 4885263      76 YRVVLIGEQGVGKSTL-----ANIFAGVHDSMDsdcevlgEDTYERTLMVDGESATIILLDmweNKGENEW--LHDHCMQ 148
Cdd:smart00010   3 YKLVVLGGGGVGKSALtiqfvQGHFVDEYDPTI-------EDSYRKQIEIDGEVCLLDILD---TAGQEEFsaMRDQYMR 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263     149 VGDAYLIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNV 228
Cdd:smart00010  73 TGEGFLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKERINV 152

                          170
                   ....*....|....
gi 4885263     229 KELFEGIVRQVRLR 242
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 4885263     77 RVVLIGEQGVGKSTLA-----NIFAGVHDSmdsdceVLGEDTYERTLMVDGEsatIILLDMWENKGENEW--LHDHCMQV 149
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLirftqNKFPEEYIP------TIGVDFYTKTIEVDGK---TVKLQIWDTAGQERFraLRPLYYRG 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263    150 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 229
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEILRHAD-ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVE 150

                         170
                  ....*....|.
gi 4885263    230 ELFEGIVRQVR 240
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 4885263   76 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLMVDGESAtiiLLDMWENKGENEW--LHDHCMQVGDAY 153
Cdd:cd04138   2 YKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTI--EDSYRKQVVIDGETC---LLDILDTAGQEEYsaMRDQYMRTGEGF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLvRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 233
Cdd:cd04138  77 LCVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDL-AARTVSTRQGQDLAKSYGIPYIETSAKTRQGVEEAFY 155

                ....*..
gi 4885263  234 GIVRQVR 240
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 4885263   77 RVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlgEDTYERTLMVDGESATIILLDmweNKGENEW--LHDHCMQVGDAYL 154
Cdd:cd04144   1 KLVVLGDGGVGKTALTIQLCLNHFVETYDPTI--EDSYRKQVVVDGQPCMLEVLD---TAGQEEYtaLRDQWIREGEGFI 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  155 IVYSITDRASFEKASELRIQLRRARQTE--DIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELF 232
Cdd:cd04144  76 LVYSITSRSTFERVERFREQIQRVKDESaaDVPIMIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNVNVERAF 155

                       170       180
                ....*....|....*....|....*...
gi 4885263  233 EGIVRQVRLRRDSKEKNERRLAYQKRKE 260
Cdd:cd04144 156 YTLVRALRQQRQGGQGPKGGPTKKKEKK 183

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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLMVDGESatiILLDMWENKGENEW--LHDHCMQVGDAY 153
Cdd:cd04139   1 HKVIMVGSGGVGKSALTLQF--MYDEFVEDYEPTKADSYRKKVVLDGEE---VQLNILDTAGQEDYaaIRDNYFRSGEGF 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 233
Cdd:cd04139  76 LLVFSITDMESFTALAEFREQILRVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFF 155

                ....*..
gi 4885263  234 GIVRQVR 240
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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLMVDGESATIILLDmweNKGENEW--LHDHCMQVGDAY 153
Cdd:cd04176   2 YKVVVLGSGGVGKSALTVQF--VSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILD---TAGTEQFasMRDLYIKNGQGF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVKELFE 233
Cdd:cd04176  77 IVVYSLVNQQTFQDIKPMRDQIVRVKGYEKVPIILVGNKVDLESEREVSSAEGRALAEEWGCPFMETSAKSKTMVNELFA 156

                ....*.
gi 4885263  234 GIVRQV 239
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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEV-LGEDTYERTLMVDGESatiILLDMWenkgenewlhDHCMQ-----V 149
Cdd:cd00154   1 FKIVLIGDSGVGKTSLLLRF--VDNKFSENYKStIGVDFKSKTIEVDGKK---VKLQIW----------DTAGQerfrsI 65

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  150 GDAY-------LIVYSITDRASFEKASELRIQLRRaRQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSA 222
Cdd:cd00154  66 TSSYyrgahgaILVYDVTNRESFENLDKWLNELKE-YAPPNIPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSA 144

                       170
                ....*....|....*
gi 4885263  223 AVQHNVKELFEGIVR 237
Cdd:cd00154 145 KTGENVDEAFESLAR 159

RSR1/Bud1p family GTPase; RSR1/Bud1p is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, RSR1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with RSR1 in vivo. In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, RSR1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton. 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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDTYERTLMVDGESATIILLDmweNKGENEW--LHDHCMQVGDAY 153
Cdd:cd04177   2 YKIVVLGAGGVGKSALTVQF--VQNVFIESYDPTIEDSYRKQVEIDGRQCDLEILD---TAGTEQFtaMRELYIKSGQGF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVF-DCKFIETSAAVQHNVKELF 232
Cdd:cd04177  77 LLVYSVTSEASLNELGELREQVLRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQWgNVPFYETSARKRTNVDEVF 156

                ....*...
gi 4885263  233 EGIVRQVR 240
Cdd:cd04177 157 IDLVRQII 164

Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families; RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263   78 VVLIGEQGVGKST-----LANIFAGVHDSMDsdcevlgEDTYERTLMVDGESATIILLDM--WENKGENEWLhDHCMQVG 150
Cdd:cd04146   2 IAVLGASGVGKSAltvrfLTKRFIGEYEPNL-------ESLYSRQVTIDGEQVSLEIQDTpgQQQNEDPESL-ERSLRWA 73

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  151 DAYLIVYSITDRASFEKASELRIQLRRARQTE-DIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQ-HNV 228
Cdd:cd04146  74 DGFVLVYSITDRSSFDVVSQLLQLIREIKKRDgEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENyLEV 153

                       170
                ....*....|..
gi 4885263  229 KELFEGIVRQVR 240
Cdd:cd04146 154 QNVFHELCREVR 165

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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDSDCEVLGEDT-YERTLMVDGESATiilLDMWENKGENEWlhdHCM-----QV 149
Cdd:cd04123   1 FKVVLLGEGRVGKTSLVLRY--VENKFNEKHESTTQASfFQKTVNIGGKRID---LAIWDTAGQERY---HALgpiyyRD 72

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  150 GDAYLIVYSITDRASFEKASELRIQLRRARQtEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQHNVK 229
Cdd:cd04123  73 ADGAILVYDITDADSFQKVKKWIKELKQMRG-NNISLVIVGNKIDLERQRVVSKSEAEEYAKSVGAKHFETSAKTGKGIE 151

                       170
                ....*....|
gi 4885263  230 ELFEGIVRQV 239
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 4885263   76 YRVVLIGEQGVGKSTLANIFagVHDSMDsdcevlgeDTYERTLMVDGESATI------ILLDMWENKGENE-------WL 142
Cdd:cd01861   1 HKLVFLGDQSVGKTSIITRF--MYDTFD--------NQYQATIGIDFLSKTMyvddktVRLQLWDTAGQERfrslipsYI 70

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  143 HDHCMQVgdaylIVYSITDRASFEKASELrIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSA 222
Cdd:cd01861  71 RDSSVAV-----VVYDITNRQSFDNTDKW-IDDVRDERGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSA 144

                       170
                ....*....|...
gi 4885263  223 AVQHNVKELFEGI 235
Cdd:cd01861 145 KAGHNVKQLFKKI 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 4885263   76 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDCEVlGEDTYERTLMVDGEsatIILLDMWENKGENEWLhdhcmQVGDAY-- 153
Cdd:cd01868   4 FKIVLIGDSGVGKSNLLSRFTRNEFNLDSKSTI-GVEFATRTIQIDGK---TIKAQIWDTAGQERYR-----AITSAYyr 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 -----LIVYSITDRASFEKA----SELRiqlrrARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAV 224
Cdd:cd01868  75 gavgaLLVYDITKKSTFENVerwlKELR-----DHADSNIVIMLVGNKSDLRHLRAVPTEEAKAFAEKNGLSFIETSALD 149

                       170
                ....*....|....*
gi 4885263  225 QHNVKELFEGIVRQV 239
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 4885263   76 YRVVLIGEQGVGKSTLAN-----IFAGVHDSmdsdceVLGEDTYERtlMVDGESATIILLDMWENKGENEWlhdhcMQVG 150
Cdd:cd04111   3 FRLIVIGDSTVGKSSLLKrftegRFAEVSDP------TVGVDFFSR--LIEIEPGVRIKLQLWDTAGQERF-----RSIT 69

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  151 DAY-------LIVYSITDRASFEKASELRIQLRRARQTEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAA 223
Cdd:cd04111  70 RSYyrnsvgvLLVFDITNRESFEHVHDWLEEARSHIQPHRPVFILVGHKCDLESQRQVTREEAEKLAKDLGMKYIETSAR 149

                       170       180
                ....*....|....*....|....
gi 4885263  224 VQHNVKELFEGIVRQVRLRRDSKE 247
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 4885263   76 YRVVLIGEQGVGKSTLanIFAGVHDSM-DSDCEVLGEDTYERTLMVDGESatiILLDMWENKGEnEWLHdhcmQVGDAY- 153
Cdd:cd01867   4 FKLLLIGDSGVGKSCL--LLRFSEDSFnPSFISTIGIDFKIRTIELDGKK---IKLQIWDTAGQ-ERFR----TITTSYy 73

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263  154 ------LIVYSITDRASFEkasELRIQLRRARQ--TEDIPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQ 225
Cdd:cd01867  74 rgamgiILVYDITDEKSFE---NIKNWMRNIDEhaSEDVERMLVGNKCDMEEKRVVSKEEGEALAREYGIKFLETSAKAN 150

                       170
                ....*....|....*..
gi 4885263  226 HNVKELFEGIVRQVRLR 242
Cdd:cd01867 151 INVEEAFLTLAKDILKK 167

Rab GTPase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263    76 YRVVLIGEQGVGKSTLANIFAGVHDSMDSDcEVLGEDTYERTLMVDGESatiILLDMWENKGENEWlhdhcMQVGDAY-- 153
Cdd:PLN03110  13 FKIVLIGDSGVGKSNILSRFTRNEFCLESK-STIGVEFATRTLQVEGKT---VKAQIWDTAGQERY-----RAITSAYyr 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4885263   154 -----LIVYSITDRASFEKASELriqLRRARQTED--IPIILVGNKSDLVRCREVSVSEGRACAVVFDCKFIETSAAVQH 226
Cdd:PLN03110  84 gavgaLLVYDITKRQTFDNVQRW---LRELRDHADsnIVIMMAGNKSDLNHLRSVAEEDGQALAEKEGLSFLETSALEAT 160