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 568933114   308 PELKVGIVGNLSSGKSALVHRYLTGTYVQEESP--EGGrFKKEIVVDGQSYLLLIRDEGGppELQFAAWVD-------AV 378
Cdd:smart00010   1 REYKLVVLGGGGVGKSALTIQFVQGHFVDEYDPtiEDS-YRKQIEIDGEVCLLDILDTAG--QEEFSAMRDqymrtgeGF 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114   379 VFVFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQ-DAIsaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVE 457
Cdd:smart00010  78 LLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKcDLE---NERVVSTEEGKELARQWG-CPFLETSAKERINVD 153

                          170
                   ....*....|....*.
gi 568933114   458 RVFQDVaqkVVALRKK 473
Cdd:smart00010 154 EAFYDL---VREIRKS 166

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWV---DA 377
Cdd:COG1100    3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFretrqFYARQLtgaSL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 378 VVFVFSLEDEISFQTVYNYFLRLcsFRNASEVPMVLVGTQ-DAISaaNPRVIDDSRARKLSTDLKRCTYYETCATYGLNV 456
Cdd:COG1100   83 YLFVVDGTREETLQSLYELLESL--RRLGKKSPIILVLNKiDLYD--EEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                 ....*....
gi 568933114 457 ERVFQDVAQ 465
Cdd:COG1100  159 EELFAALAE 167

Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases); The Ras family of the Ras superfamily includes classical N-Ras, H-Ras, and K-Ras, as well as R-Ras, Rap, Ral, Rheb, Rhes, ARHI, RERG, Rin/Rit, RSR1, RRP22, Ras2, Ras-dva, and RGK proteins. Ras proteins regulate cell growth, proliferation and differentiation. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These 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: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs 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 568933114 311 KVGIVGNLSSGKSALVHRYLTGTYVQEESP-EGGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVFSL 384
Cdd:cd00876    1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPtIEDSYRKQIVVDGETYTLDILDTAGQEEFsamrdQYIRNGDGFILVYSI 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 385 EDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQDVA 464
Cdd:cd00876   81 TSRESFEEIKNIREQILRVKDKEDVPIVLVGNK--CDLENERQVSTEEGEALAEEWG-CPFLETSAKTNINIDELFNTLV 157

                 ...
gi 568933114 465 QKV 467
Cdd:cd00876  158 REI 160

Rap-like family consists of Rap1, Rap2 and RSR1; The Rap subfamily consists of the Rap1, Rap2, and RSR1. Rap subfamily proteins perform different cellular functions, depending on the isoform and its subcellular localization. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and microsomal membrane of the pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. Rap1 localizes in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap2 is involved in multiple functions, including activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton and activation of the Wnt/beta-catenin signaling pathway in embryonic Xenopus. A number of effector proteins for Rap2 have been identified, including isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK), and the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. RSR1 is the fungal homolog of Rap1 and Rap2. In budding yeasts, it is involved in selecting a site for bud growth, which directs the establishment of cell polarization. The Rho family GTPase Cdc42 and its GEF, Cdc24, then establish an axis of polarized growth. It is believed that Cdc42 interacts directly with RSR1 in vivo. In filamentous fungi such as Ashbya gossypii, RSR1 is a key regulator of polar growth in the hypha. 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 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPelQFAAWVD-------AVVF 380
Cdd:cd04136    1 EYKLVVLGSGGVGKSALTVQFVQGIFVDKYDPTiEDSYRKQIEVDCQQCMLEILDTAGTE--QFTAMRDlyikngqGFAL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 381 VFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVF 460
Cdd:cd04136   79 VYSITAQQSFNDLQDLREQILRVKDTEDVPMILVGNK--CDLEDERVVSKEEGQNLARQWGNCPFLETSAKSKINVDEIF 156

                 ....*..
gi 568933114 461 QDVAQKV 467
Cdd:cd04136  157 YDLVRQI 163

Rab GTPase family 7 (Rab7); Rab7 subfamily. Rab7 is a small Rab GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. The yeast Ypt7 and mammalian Rab7 are both involved in transport to the vacuole/lysosome, whereas Ypt7 is also required for homotypic vacuole fusion. Mammalian Rab7 is an essential participant in the autophagic pathway for sequestration and targeting of cytoplasmic components to the lytic compartment. Mammalian Rab7 is also proposed to function as a tumor suppressor. 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 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTYVQE-ESPEGGRF-KKEIVVDGQSYLLLIRDEGGPPELQ-----FAAWVDAVVFVF 382
Cdd:cd01862    1 LKVIILGDSGVGKTSLMNQYVNKKFSNQyKATIGADFlTKEVTVDDRLVTLQIWDTAGQERFQslgvaFYRGADCCVLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 383 SLEDEISFQTVYNY---FLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERV 459
Cdd:cd01862   81 DVTNPKSFESLDSWrdeFLIQASPRDPENFPFVVLGNK--IDLEEKRQVSTKKAQQWCKSKGNIPYFETSAKEAINVDQA 158

                        170
                 ....*....|...
gi 568933114 460 FQDVAQKVVALRK 472
Cdd:cd01862  159 FETIARLALEQEK 171

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 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFK-KEIVVDGQSYLLLIRDEGGppelQ--FAAWV-------DAV 378
Cdd:cd00154    1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTiGVDFKsKTIEVDGKKVKLQIWDTAG----QerFRSITssyyrgaHGA 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 379 VFVFSLEDEISFQTVYNYFLRLCSFRNaSEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVER 458
Cdd:cd00154   77 ILVYDVTNRESFENLDKWLNELKEYAP-PNIPIILVGNK--SDLEDERQVSTEEAQQFAKENG-LLFFETSAKTGENVDE 152

                 ....*..
gi 568933114 459 VFQDVAQ 465
Cdd:cd00154  153 AFESLAR 159

Rap1 family GTPase consists of Rap1a and Rap1b isoforms; The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature. Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and the microsomal membrane of pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment of Cdc42, which is required for formation of dendrites and axons. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation. 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 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPelQFAAWVD-------AVVF 380
Cdd:cd04175    1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTiEDSYRKQVEVDGQQCMLEILDTAGTE--QFTAMRDlymkngqGFVL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 381 VFSLEDEISF---QTVYNYFLRLcsfRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVE 457
Cdd:cd04175   79 VYSITAQSTFndlQDLREQILRV---KDTEDVPMILVGNK--CDLEDERVVGKEQGQNLARQWG-CAFLETSAKAKINVN 152

                        170
                 ....*....|
gi 568933114 458 RVFQDVAQKV 467
Cdd:cd04175  153 EIFYDLVRQI 162

Rat sarcoma (Ras)-like superfamily of small guanosine triphosphatases (GTPases); Ras-like GTPase superfamily. The Ras-like superfamily of small GTPases consists of several families with an extremely high degree of structural and functional similarity. The Ras superfamily is divided into at least four families in eukaryotes: the Ras, Rho, Rab, and Sar1/Arf families. This superfamily also includes proteins like the GTP translation factors, Era-like GTPases, and G-alpha chain of the heterotrimeric G proteins. Members of the Ras superfamily regulate a wide variety of cellular functions: the Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. The GTP translation factor family regulates initiation, elongation, termination, and release in translation, and the Era-like GTPase family regulates cell division, sporulation, and DNA replication. Members of the Ras superfamily are identified by the GTP binding site, which is made up of five characteristic sequence motifs, and the switch I and switch II regions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 313 GIVGNLSSGKSALVHRYLTGTYVQEESPEG---GRFKKEIVVDGQSYLLLIRDEGGPPE----------LQFAAWVDAVV 379
Cdd:cd00882    1 VVVGRGGVGKSSLLNALLGGEVGEVSDVPGttrDPDVYVKELDKGKVKLVLVDTPGLDEfgglgreelaRLLLRGADLIL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 380 FVFSLEDEISFQTVYNYFLRLcsfRNASEVPMVLVGTQ-DAISAANPRVIDDSRARKLSTDLKrctYYETCATYGLNVER 458
Cdd:cd00882   81 LVVDSTDRESEEDAKLLILRR---LRKEGIPIILVGNKiDLLEEREVEELLRLEELAKILGVP---VFEVSAKTGEGVDE 154

                 ....*..
gi 568933114 459 VFQDVAQ 465
Cdd:cd00882  155 LFEKLIE 161

Ras Homolog Enriched in Brain (RheB) is a small GTPase; Rheb (Ras Homolog Enriched in Brain) subfamily. Rheb was initially identified in rat brain, where its expression is elevated by seizures or by long-term potentiation. It is expressed ubiquitously, with elevated levels in muscle and brain. Rheb functions as an important mediator between the tuberous sclerosis complex proteins, TSC1 and TSC2, and the mammalian target of rapamycin (TOR) kinase to stimulate cell growth. TOR kinase regulates cell growth by controlling nutrient availability, growth factors, and the energy status of the cell. TSC1 and TSC2 form a dimeric complex that has tumor suppressor activity, and TSC2 is a GTPase activating protein (GAP) for Rheb. The TSC1/TSC2 complex inhibits the activation of TOR kinase through Rheb. Rheb has also been shown to induce the formation of large cytoplasmic vacuoles in a process that is dependent on the GTPase cycle of Rheb, but independent of the TOR kinase, suggesting Rheb plays a role in endocytic trafficking that leads to cell growth and cell-cycle progression. 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 568933114 311 KVGIVGNLSSGKSALVHRYLTGTYVQEESP--EgGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVFS 383
Cdd:cd04137    3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPtiE-NTFSKIITYKGQEYHLEIVDTAGQDEYsilpqKYSIGIHGYILVYS 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 568933114 384 LEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVF 460
Cdd:cd04137   82 VTSRKSFEVVKVIYDKILDMLGKESVPIVLVGNKSDLH--MERQVSAEEGKKLAESWG-AAFLESSAKENENVEEAF 155

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 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 382
Cdd:cd04138    1 EYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTiEDSYRKQVVIDGETCLLDILDTAGQEEYsamrdQYMRTGEGFLCVF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 383 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAanpRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 462
Cdd:cd04138   81 AINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDLAA---RTVSTRQGQDLAKSYG-IPYIETSAKTRQGVEEAFYT 156

                 ....*
gi 568933114 463 VAQKV 467
Cdd:cd04138  157 LVREI 161

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWV---DA 377
Cdd:COG1100    3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFretrqFYARQLtgaSL 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 378 VVFVFSLEDEISFQTVYNYFLRLcsFRNASEVPMVLVGTQ-DAISaaNPRVIDDSRARKLSTDLKRCTYYETCATYGLNV 456
Cdd:COG1100   83 YLFVVDGTREETLQSLYELLESL--RRLGKKSPIILVLNKiDLYD--EEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                 ....*....
gi 568933114 457 ERVFQDVAQ 465
Cdd:COG1100  159 EELFAALAE 167

Rab GTPase family 23 (Rab23)-like; Rab23-like subfamily. Rab23 is a member of the Rab family of small GTPases. In mouse, Rab23 has been shown to function as a negative regulator in the sonic hedgehog (Shh) signaling pathway. Rab23 mediates the activity of Gli2 and Gli3, transcription factors that regulate Shh signaling in the spinal cord, primarily by preventing Gli2 activation in the absence of Shh ligand. Rab23 also regulates a step in the cytoplasmic signal transduction pathway that mediates the effect of Smoothened (one of two integral membrane proteins that are essential components of the Shh signaling pathway in vertebrates). In humans, Rab23 is expressed in the retina. Mice contain an isoform that shares 93% sequence identity with the human Rab23 and an alternative splicing isoform that is specific to the brain. This isoform causes the murine open brain phenotype, indicating it may have a role in the development of the central nervous system. 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 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTYVQEespeggrFKKEIVVD-----------GQSYLLLIRDEGGPPElqFAAWVD-- 376
Cdd:cd04106    1 IKVIVVGNGNVGKSSMIQRFVKGIFTKD-------YKKTIGVDflekqiflrqsDEDVRLMLWDTAGQEE--FDAITKay 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 377 -----AVVFVFSLEDEISFQTVYNYflRLCSFRNASEVPMVLVgtQDAISAANPRVIDDSRARKLSTDLKrCTYYETCAT 451
Cdd:cd04106   72 yrgaqACILVFSTTDRESFEAIESW--KEKVEAECGDIPMVLV--QTKIDLLDQAVITNEEAEALAKRLQ-LPLFRTSVK 146

                        170
                 ....*....|....*
gi 568933114 452 YGLNVERVFQDVAQK 466
Cdd:cd04106  147 DDFNVTELFEYLAEK 161

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 382
Cdd:PTZ00369   5 EYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTiEDSYRKQCVIDEETCLLDILDTAGQEEYsamrdQYMRTGQGFLCVY 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 383 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 462
Cdd:PTZ00369  85 SITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDLD--SERQVSTGEGQELAKSFG-IPFLETSAKQRVNVDEAFYE 161

                 ....*
gi 568933114 463 VAQKV 467
Cdd:PTZ00369 162 LVREI 166

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 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTY----VQEESPEGGrfKKEIVVDGQSYLLLIRDeggPPELQFAAWV--------DA 377
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFTAGVYedsaYEASGDDTY--ERTVSVDGEEATLVVYD---HWEQEDGMWLedscmqvgDA 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 378 VVFVFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAIsaANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVE 457
Cdd:cd04148   76 YVIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDL--VRSREVSVQEGRACAVVFD-CKFIETSAALQHNVD 152

                        170
                 ....*....|....*..
gi 568933114 458 RVFQD-VAQkvVALRKK 473
Cdd:cd04148  153 ELFEGiVRQ--VRLRRD 167

Ras homology family (Rho) of small guanosine triphosphatases (GTPases); Members of the Rho (Ras homology) family include RhoA, Cdc42, Rac, Rnd, Wrch1, RhoBTB, and Rop. There are 22 human Rho family members identified currently. These proteins are all involved in the reorganization of the actin cytoskeleton in response to external stimuli. They also have roles in cell transformation by Ras in cytokinesis, in focal adhesion formation and in the stimulation of stress-activated kinase. These various functions are controlled through distinct effector proteins and mediated through a GTP-binding/GTPase cycle involving three classes of regulating proteins: GAPs (GTPase-activating proteins), GEFs (guanine nucleotide exchange factors), and GDIs (guanine nucleotide dissociation inhibitors). Most Rho 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 Rho proteins. Since crystal structures often lack C-terminal residues, this feature is not available for annotation in many of the CDs in the hierarchy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTYVQEESP---EGgrFKKEIVVDGQSYLLLIRDEGGPPE------LQFAAwVDAVVF 380
Cdd:cd00157    1 IKIVVVGDGAVGKTCLLISYTTNKFPTEYVPtvfDN--YSANVTVDGKQVNLGLWDTAGQEEydrlrpLSYPQ-TDVFLL 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 381 VFSLEDEISFQTVYNYF---LRlcsfRNASEVPMVLVGTQ-DAISAANPRV--------IDDSRARKLSTDLKRCTYYET 448
Cdd:cd00157   78 CFSVDSPSSFENVKTKWypeIK----HYCPNVPIILVGTKiDLRDDGNTLKklekkqkpITPEEGEKLAKEIGAVKYMEC 153

                        170
                 ....*....|....*..
gi 568933114 449 CATYGLNVERVFQDVAQ 465
Cdd:cd00157  154 SALTQEGLKEVFDEAIR 170

Ras-like protein in all tissues (Rit), Ras-like protein in neurons (Rin) and Ras-related protein which interacts with calmodulin (Ric); Rit (Ras-like protein in all tissues), Rin (Ras-like protein in neurons) and Ric (Ras-related protein which interacts with calmodulin) form a subfamily with several unique structural and functional characteristics. These proteins all lack a the C-terminal CaaX lipid-binding motif typical of Ras family proteins, and Rin and Ric contain calmodulin-binding domains. Rin, which is expressed only in neurons, induces neurite outgrowth in rat pheochromocytoma cells through its association with calmodulin and its activation of endogenous Rac/cdc42. Rit, which is ubiquitously expressed in mammals, inhibits growth-factor withdrawl-mediated apoptosis and induces neurite extension in pheochromocytoma cells. Rit and Rin are both able to form a ternary complex with PAR6, a cell polarity-regulating protein, and Rac/cdc42. This ternary complex is proposed to have physiological function in processes such as tumorigenesis. Activated Ric is likely to signal in parallel with the Ras pathway or stimulate the Ras pathway at some upstream point, and binding of calmodulin to Ric may negatively regulate Ric activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 309 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 382
Cdd:cd04141    2 EYKIVMLGAGGVGKSAVTMQFISHSFPDYHDPTiEDAYKTQARIDNEPALLDILDTAGQAEFtamrdQYMRCGEGFIICY 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 383 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 462
Cdd:cd04141   82 SVTDRHSFQEASEFKELITRVRLTEDIPLVLVGNK--VDLEQQRQVTTEEGRNLAREFN-CPFFETSAALRFYIDDAFHG 158

                        170
                 ....*....|....*
gi 568933114 463 VAQKVvalRKKQQLA 477
Cdd:cd04141  159 LVREI---RRKESMP 170

Rab GTPase family 27a (Rab27a); The Rab27a subfamily consists of Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4. Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy. When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers. 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 568933114 310 LKVGIVGNLSSGKSALVHRYLTGTY-VQEESPEGGRFKKEIVV-----------DGQSYLLLIRDEGGPPE---LQFAAW 374
Cdd:cd04127    5 IKLLALGDSGVGKTTFLYRYTDNKFnPKFITTVGIDFREKRVVynsqgpdgtsgKAFRVHLQLWDTAGQERfrsLTTAFF 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114 375 VDAVVF--VFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLkRCTYYETCATY 452
Cdd:cd04127   85 RDAMGFllMFDLTSEQSFLNVRNWMSQLQAHAYCENPDIVLIGNKADLP--DQREVSERQARELADKY-GIPYFETSAAT 161

                 ....*.
gi 568933114 453 GLNVER 458
Cdd:cd04127  162 GQNVEK 167

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 568933114 311 KVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGP---PELQFAAWVD--AVVFVFSL 384
Cdd:cd04140    3 RVVVFGAGGVGKSSLVLRFVKGTFRESYIPTiEDTYRQVISCSKSICTLQITDTTGShqfPAMQRLSISKghAFILVYSI 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568933114 385 EDEISFQTVYNYFLRLCSFR--NASEVPMVLVGTQDAISAAnpRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQ 461
Cdd:cd04140   83 TSKQSLEELKPIYELICEIKgnNLEKIPIMLVGNKCDESPS--REVSSSEGAALARTWN-CAFMETSAKTNHNVQELFQ 158

Ras of Complex, Roc, domain of DAPkinase; Roc, or Ras of Complex, proteins are mitochondrial Rho proteins (Miro-1, and Miro-2) and atypical Rho GTPases. Full-length proteins have a unique domain organization, with tandem GTP-binding domains and two EF hand domains (pfam00036) that may bind calcium. They are also larger than classical small GTPases. It has been proposed that they are involved in mitochondrial homeostasis and apoptosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568933114  311 KVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGrfkkeivVDGQSYLLLIRDEGGpPELQFAAW---------------- 374
Cdd:pfam08477   1 KVVLLGDSGVGKTSLLKRFVDDTFDPKYKSTIG-------VDFKTKTVLENDDNG-KKIKLNIWdtagqerfrslhpfyy 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 568933114  375 --VDAVVFVFsleDEISFQTVYNYFLRLCsfRNASEVPMVLVGT 416
Cdd:pfam08477  73 rgAAAALLVY---DSRTFSNLKYWLRELK--KYAGNSPVILVGN 111