Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 387
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462612282 388 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 465
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 387
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462612282 388 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 465
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

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 2462612282  306 PELKVGIVGNLSSGKSALVHRYLTGTYVQEESP--EGGrFKKEIVVDGQSYLLLIRDEGGppELQFAAWVD-------AV 376
Cdd:smart00010   1 REYKLVVLGGGGVGKSALTIQFVQGHFVDEYDPtiEDS-YRKQIEIDGEVCLLDILDTAG--QEEFSAMRDqymrtgeGF 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282  377 VFVFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQ-DAIsaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVE 455
Cdd:smart00010  78 LLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKcDLE---NERVVSTEEGKELARQWG-CPFLETSAKERINVD 153

                          170
                   ....*....|....*.
gi 2462612282  456 RVFQDVaqkVVALRKK 471
Cdd:smart00010 154 EAFYDL---VREIRKS 166

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWV---DA 375
Cdd:COG1100     3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFretrqFYARQLtgaSL 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 376 VVFVFSLEDEISFQTVYNYFLRLcsFRNASEVPMVLVGTQ-DAISaaNPRVIDDSRARKLSTDLKRCTYYETCATYGLNV 454
Cdd:COG1100    83 YLFVVDGTREETLQSLYELLESL--RRLGKKSPIILVLNKiDLYD--EEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                  ....*....
gi 2462612282 455 ERVFQDVAQ 463
Cdd:COG1100   159 EELFAALAE 167

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462612282  584 PIKQGILLKRSGKSlNKEWKKKYVTLCdNGLLTYHPSLHDYMQNIHGKEIDLLRTTVKVPGKRLPRATP 652
Cdd:smart00233   1 VIKEGWLYKKSGGG-KKSWKKRYFVLF-NSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSSKKP 67

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQFAAWVDAVVFVFSLEDEIS 387
Cdd:cd04103     1 LKLGIVGNLRSGKSALVHRYLTGSYVQLESPEGGRFKKEVLVDGQSHLLLIRDEGGAPDAQFAGWVDAVIFVFSLEDEAS 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462612282 388 FQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVFQDVAQKV 465
Cdd:cd04103    81 FQTVYRLYHQLSSYRNISEIPLILVGTQDAISASNPRVIDDARARQLCADMKRCSYYETCATYGLNVERVFQEAAQKI 158

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 2462612282 309 KVGIVGNLSSGKSALVHRYLTGTYVQEESP-EGGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVFSL 382
Cdd:cd00876     1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPtIEDSYRKQIVVDGETYTLDILDTAGQEEFsamrdQYIRNGDGFILVYSI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 383 EDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQDVA 462
Cdd:cd00876    81 TSRESFEEIKNIREQILRVKDKEDVPIVLVGNK--CDLENERQVSTEEGEALAEEWG-CPFLETSAKTNINIDELFNTLV 157

                  ...
gi 2462612282 463 QKV 465
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 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPelQFAAWVD-------AVVF 378
Cdd:cd04136     1 EYKLVVLGSGGVGKSALTVQFVQGIFVDKYDPTiEDSYRKQIEVDCQQCMLEILDTAGTE--QFTAMRDlyikngqGFAL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 379 VFSLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERVF 458
Cdd:cd04136    79 VYSITAQQSFNDLQDLREQILRVKDTEDVPMILVGNK--CDLEDERVVSKEEGQNLARQWGNCPFLETSAKSKINVDEIF 156

                  ....*..
gi 2462612282 459 QDVAQKV 465
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 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQE-ESPEGGRF-KKEIVVDGQSYLLLIRDEGGPPELQ-----FAAWVDAVVFVF 380
Cdd:cd01862     1 LKVIILGDSGVGKTSLMNQYVNKKFSNQyKATIGADFlTKEVTVDDRLVTLQIWDTAGQERFQslgvaFYRGADCCVLVY 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 381 SLEDEISFQTVYNY---FLRLCSFRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKRCTYYETCATYGLNVERV 457
Cdd:cd01862    81 DVTNPKSFESLDSWrdeFLIQASPRDPENFPFVVLGNK--IDLEEKRQVSTKKAQQWCKSKGNIPYFETSAKEAINVDQA 158

                         170
                  ....*....|...
gi 2462612282 458 FQDVAQKVVALRK 470
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 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFK-KEIVVDGQSYLLLIRDEGGppelQ--FAAWV-------DAV 376
Cdd:cd00154     1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTiGVDFKsKTIEVDGKKVKLQIWDTAG----QerFRSITssyyrgaHGA 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 377 VFVFSLEDEISFQTVYNYFLRLCSFRNaSEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVER 456
Cdd:cd00154    77 ILVYDVTNRESFENLDKWLNELKEYAP-PNIPIILVGNK--SDLEDERQVSTEEAQQFAKENG-LLFFETSAKTGENVDE 152

                  ....*..
gi 2462612282 457 VFQDVAQ 463
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 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPelQFAAWVD-------AVVF 378
Cdd:cd04175     1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTiEDSYRKQVEVDGQQCMLEILDTAGTE--QFTAMRDlymkngqGFVL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 379 VFSLEDEISF---QTVYNYFLRLcsfRNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCATYGLNVE 455
Cdd:cd04175    79 VYSITAQSTFndlQDLREQILRV---KDTEDVPMILVGNK--CDLEDERVVGKEQGQNLARQWG-CAFLETSAKAKINVN 152

                         170
                  ....*....|
gi 2462612282 456 RVFQDVAQKV 465
Cdd:cd04175   153 EIFYDLVRQI 162

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 2462612282 309 KVGIVGNLSSGKSALVHRYLTGTYVQE-ESPEGGRFKKEIVVDGQSYLLLIRDEGGPPELQ-------FAAWVDAVVFVF 380
Cdd:cd04146     1 KIAVLGASGVGKSALTVRFLTKRFIGEyEPNLESLYSRQVTIDGEQVSLEIQDTPGQQQNEdpeslerSLRWADGFVLVY 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 381 SLEDEISFQTV--YNYFLRLCSfRNASEVPMVLVGT-QDaisAANPRVIDDSRARKLSTDLkRCTYYE--TCATYgLNVE 455
Cdd:cd04146    81 SITDRSSFDVVsqLLQLIREIK-KRDGEIPVILVGNkAD---LLHSRQVSTEEGQKLALEL-GCLFFEvsAAENY-LEVQ 154

                         170
                  ....*....|
gi 2462612282 456 RVFQDVAQKV 465
Cdd:cd04146   155 NVFHELCREV 164

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 2462612282 309 KVGIVGNLSSGKSALVHRYLTGTYVQEESP--EgGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVFS 381
Cdd:cd04137     3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPtiE-NTFSKIITYKGQEYHLEIVDTAGQDEYsilpqKYSIGIHGYILVYS 81

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2462612282 382 LEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVF 458
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 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 380
Cdd:cd04138     1 EYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTiEDSYRKQVVIDGETCLLDILDTAGQEEYsamrdQYMRTGEGFLCVF 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 381 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISAanpRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 460
Cdd:cd04138    81 AINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDLAA---RTVSTRQGQDLAKSYG-IPYIETSAKTRQGVEEAFYT 156

                  ....*
gi 2462612282 461 VAQKV 465
Cdd:cd04138   157 LVREI 161

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEE--SPEG-GRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWV---DA 375
Cdd:COG1100     3 EKKIVVVGTGGVGKTSLVNRLVGDIFSLEKylSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFretrqFYARQLtgaSL 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 376 VVFVFSLEDEISFQTVYNYFLRLcsFRNASEVPMVLVGTQ-DAISaaNPRVIDDSRARKLSTDLKRCTYYETCATYGLNV 454
Cdd:COG1100    83 YLFVVDGTREETLQSLYELLESL--RRLGKKSPIILVLNKiDLYD--EEEIEDEERLKEALSEDNIVEVVATSAKTGEGV 158

                  ....*....
gi 2462612282 455 ERVFQDVAQ 463
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 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEespeggrFKKEIVVD-----------GQSYLLLIRDEGGPPElqFAAWVD-- 374
Cdd:cd04106     1 IKVIVVGNGNVGKSSMIQRFVKGIFTKD-------YKKTIGVDflekqiflrqsDEDVRLMLWDTAGQEE--FDAITKay 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 375 -----AVVFVFSLEDEISFQTVYNYflRLCSFRNASEVPMVLVgtQDAISAANPRVIDDSRARKLSTDLKrCTYYETCAT 449
Cdd:cd04106    72 yrgaqACILVFSTTDRESFEAIESW--KEKVEAECGDIPMVLV--QTKIDLLDQAVITNEEAEALAKRLQ-LPLFRTSVK 146

                         170
                  ....*....|....*
gi 2462612282 450 YGLNVERVFQDVAQK 464
Cdd:cd04106   147 DDFNVTELFEYLAEK 161

Ras-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 307 ELKVGIVGNLSSGKSALVHRYLTGTYVQEESPE-GGRFKKEIVVDGQSYLLLIRDEGGPPEL-----QFAAWVDAVVFVF 380
Cdd:PTZ00369    5 EYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTiEDSYRKQCVIDEETCLLDILDTAGQEEYsamrdQYMRTGQGFLCVY 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 381 SLEDEISFQTVYNYFLRLCSFRNASEVPMVLVGTQDAISaaNPRVIDDSRARKLSTDLKrCTYYETCATYGLNVERVFQD 460
Cdd:PTZ00369   85 SITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDLD--SERQVSTGEGQELAKSFG-IPFLETSAKQRVNVDEAFYE 161

                  ....*
gi 2462612282 461 VAQKV 465
Cdd:PTZ00369  162 LVREI 166

Rab GTPase family J-like (RabJ-like); RJLs are found in many protists and as chimeras with C-terminal DNAJ domains in deuterostome metazoa. They are not found in plants, fungi, and protostome metazoa, suggesting a horizontal gene transfer between protists and deuterostome metazoa. RJLs lack any known membrane targeting signal and contain a degenerate phosphate/magnesium-binding 3 (PM3) motif, suggesting an impaired ability to hydrolyze GTP. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGG---------RFKKEIVVD-----GQSYLLLIRDEggppelqFAAWV 373
Cdd:cd04119     1 IKVISMGNSGVGKSCIIKRYCEGRFVSKYLPTIGidygvkkvsVRNKEVRVNffdlsGHPEYLEVRNE-------FYKDT 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 374 DAVVFVFSLEDEISFQTVYNYFLRLCSF----RNASEVPMVLVGTQdaISAANPRVIDDSRARKLSTDLKrCTYYETCAT 449
Cdd:cd04119    74 QGVLLVYDVTDRQSFEALDSWLKEMKQEggphGNMENIVVVVCANK--IDLTKHRAVSEDEGRLWAESKG-FKYFETSAC 150

                         170
                  ....*....|....*...
gi 2462612282 450 YGLNVERVFQDVAQKVVA 467
Cdd:cd04119   151 TGEGVNEMFQTLFSSIVD 168

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 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESP---EGgrFKKEIVVDGQSYLLLIRDEGGPPE------LQFAAwVDAVVF 378
Cdd:cd00157     1 IKIVVVGDGAVGKTCLLISYTTNKFPTEYVPtvfDN--YSANVTVDGKQVNLGLWDTAGQEEydrlrpLSYPQ-TDVFLL 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 379 VFSLEDEISFQTVYNYF---LRlcsfRNASEVPMVLVGTQ-DAISAANPRV--------IDDSRARKLSTDLKRCTYYET 446
Cdd:cd00157    78 CFSVDSPSSFENVKTKWypeIK----HYCPNVPIILVGTKiDLRDDGNTLKklekkqkpITPEEGEKLAKEIGAVKYMEC 153

                         170
                  ....*....|....*..
gi 2462612282 447 CATYGLNVERVFQDVAQ 463
Cdd:cd00157   154 SALTQEGLKEVFDEAIR 170

Septum-promoting GTPase (Spg1); Spg1p. Spg1p (septum-promoting GTPase) was first identified in the fission yeast S. pombe, where it regulates septum formation in the septation initiation network (SIN) through the cdc7 protein kinase. Spg1p is an essential gene that localizes to the spindle pole bodies. When GTP-bound, it binds cdc7 and causes it to translocate to spindle poles. Sid4p (septation initiation defective) is required for localization of Spg1p to the spindle pole body, and the ability of Spg1p to promote septum formation from any point in the cell cycle depends on Sid4p. Spg1p is negatively regulated by Byr4 and cdc16, which form a two-component GTPase activating protein (GAP) for Spg1p. The existence of a SIN-related pathway in plants has been proposed. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 308 LKVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGR--FKKEIVVDGQSYLLLIRDEGGppELQFA-----AWVDAVV--F 378
Cdd:cd04128     1 LKIGLLGDAQIGKTSLMVKYVEGEFDEEYIQTLGVnfMEKTISIRGTEITFSIWDLGG--QREFInmlplVCKDAVAilF 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 379 VFSLEDEISFQTVYNYFLRLCSFrNASEVPmVLVGTQDAISAANPRVIDD---SRARKLSTDLKrCTYYETCATYGLNVE 455
Cdd:cd04128    79 MFDLTRKSTLNSIKEWYRQARGF-NKTAIP-ILVGTKYDLFADLPPEEQEeitKQARKYAKAMK-APLIFCSTSHSINVQ 155

                         170
                  ....*....|...
gi 2462612282 456 RVFQDVAQKVVAL 468
Cdd:cd04128   156 KIFKFVLAKVFDL 168

Ras homolog enriched in striatum (Rhes) and activator of G-protein signaling 1 (Dexras1/AGS1); This subfamily includes Rhes (Ras homolog enriched in striatum) and Dexras1/AGS1 (activator of G-protein signaling 1). These proteins are homologous, but exhibit significant differences in tissue distribution and subcellular localization. Rhes is found primarily in the striatum of the brain, but is also expressed in other areas of the brain, such as the cerebral cortex, hippocampus, inferior colliculus, and cerebellum. Rhes expression is controlled by thyroid hormones. In rat PC12 cells, Rhes is farnesylated and localizes to the plasma membrane. Rhes binds and activates PI3K, and plays a role in coupling serpentine membrane receptors with heterotrimeric G-protein signaling. Rhes has recently been shown to be reduced under conditions of dopamine supersensitivity and may play a role in determining dopamine receptor sensitivity. Dexras1/AGS1 is a dexamethasone-induced Ras protein that is expressed primarily in the brain, with low expression levels in other tissues. Dexras1 localizes primarily to the cytoplasm, and is a critical regulator of the circadian master clock to photic and nonphotic input. 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 2462612282 309 KVGIVGNLSSGKSALVHRYLTGTYVQEESPEGGRF-KKEIVVDGQSYLLLIRDEGGppELQFAAWV-------DAVVFVF 380
Cdd:cd04143     2 RMVVLGASKVGKTAIVSRFLGGRFEEQYTPTIEDFhRKLYSIRGEVYQLDILDTSG--NHPFPAMRrlsiltgDVFILVF 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462612282 381 SLEDEISFQTVynyflrlCSFRN---------------ASEVPMVLVGTQDAISAanPRVIDDSRARKLSTDLKRCTYYE 445
Cdd:cd04143    80 SLDNRESFEEV-------CRLREqiletksclknktkeNVKIPMVICGNKADRDF--PREVQRDEVEQLVGGDENCAYFE 150

                         170
                  ....*....|....
gi 2462612282 446 TCATYGLNVERVFQ 459
Cdd:cd04143   151 VSAKKNSNLDEMFR 164

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462612282  584 PIKQGILLKRSGKSlNKEWKKKYVTLCdNGLLTYHPSLHDYMQNIHGKEIDLLRTTVKVPGKRLPRATP 652
Cdd:smart00233   1 VIKEGWLYKKSGGG-KKSWKKRYFVLF-NSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSSKKP 67