P-loop containing Nucleoside Triphosphate Hydrolases; Members of the P-loop NTPase domain superfamily are characterized by a conserved nucleotide phosphate-binding motif, also referred to as the Walker A motif (GxxxxGK[S/T], where x is any residue), and the Walker B motif (hhhh[D/E], where h is a hydrophobic residue). The Walker A and B motifs bind the beta-gamma phosphate moiety of the bound nucleotide (typically ATP or GTP) and the Mg2+ cation, respectively. The P-loop NTPases are involved in diverse cellular functions, and they can be divided into two major structural classes: the KG (kinase-GTPase) class which includes Ras-like GTPases and its circularly permutated YlqF-like; and the ASCE (additional strand catalytic E) class which includes ATPase Binding Cassette (ABC), DExD/H-like helicases, 4Fe-4S iron sulfur cluster binding proteins of NifH family, RecA-like F1-ATPases, and ATPases Associated with a wide variety of Activities (AAA). Also included are a diverse set of nucleotide/nucleoside kinase families.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928 147 FKVMLVGESGVGKSTLAGTF-GGLQGDSAHEPENpaEDTYERRIMVDKEEVTLVVYDIWEQGDaGGWLRDHCLQTGDAFL 225
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFtAGVYEDSAYEASG--DDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYV 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 767979928 226 IVFSVTDRRSFSKVPETLLRLRAGRPHHDLPVILVGNKSDLARSRE 271
Cdd:cd04148   78 IVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSRE 123

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 767979928 147 FKVMLVGESGVGKSTLAGTF-GGLQGDSAHEPENpaEDTYERRIMVDKEEVTLVVYDIWEQGDaGGWLRDHCLQTGDAFL 225
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFtAGVYEDSAYEASG--DDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYV 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 767979928 226 IVFSVTDRRSFSKVPETLLRLRAGRPHHDLPVILVGNKSDLARSRE 271
Cdd:cd04148   78 IVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSRE 123

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 767979928   147 FKVMLVGESGVGKSTLAGTFggLQG--DSAHEPEnpAEDTYERRIMVDKEEVTLVVYDIweqgdAG----GWLRDHCLQT 220
Cdd:smart00010   3 YKLVVLGGGGVGKSALTIQF--VQGhfVDEYDPT--IEDSYRKQIEIDGEVCLLDILDT-----AGqeefSAMRDQYMRT 73

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 767979928   221 GDAFLIVFSVTDRRSF---SKVPETLLRLRaGRphHDLPVILVGNKSDLARSRE 271
Cdd:smart00010  74 GEGFLLVYSITDRQSFeeiAKFREQILRVK-DR--DDVPIVLVGNKCDLENERV 124

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928 148 KVMLVGESGVGKSTLAGTFGGLQ-GDSAHEPENPAeDTYERRIMVDKEEVTLVVYDIweqgdAG-------GWLRDHCLQ 219
Cdd:COG1100    5 KIVVVGTGGVGKTSLVNRLVGDIfSLEKYLSTNGV-TIDKKELKLDGLDVDLVIWDT-----PGqdefretRQFYARQLT 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 767979928 220 TGDAFLIVFSVTDRRSFSKVPETLLRL-RAGRphhDLPVILVGNKSDLARSRER 272
Cdd:COG1100   79 GASLYLFVVDGTREETLQSLYELLESLrRLGK---KSPIILVLNKIDLYDEEEI 129

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 767979928 147 FKVMLVGESGVGKSTLAGTF-GGLQGDSAHEPENpaEDTYERRIMVDKEEVTLVVYDIWEQGDaGGWLRDHCLQTGDAFL 225
Cdd:cd04148    1 YRVVLLGDSGVGKSSLANIFtAGVYEDSAYEASG--DDTYERTVSVDGEEATLVVYDHWEQED-GMWLEDSCMQVGDAYV 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 767979928 226 IVFSVTDRRSFSKVPETLLRLRAGRPHHDLPVILVGNKSDLARSRE 271
Cdd:cd04148   78 IVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSRE 123

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 767979928 148 KVMLVGESGVGKSTLAGTFggLQGDSAHEPENPAEDTYERRIMVDKEEVTLVVYD-IWEQGDAGGWLRDHCLQTGDAFLI 226
Cdd:cd04146    1 KIAVLGASGVGKSALTVRF--LTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDtPGQQQNEDPESLERSLRWADGFVL 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 767979928 227 VFSVTDRRSFSKVPETLLRLRAGRPHH-DLPVILVGNKSDLARSRE 271
Cdd:cd04146   79 VYSITDRSSFDVVSQLLQLIREIKKRDgEIPVILVGNKADLLHSRQ 124

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 767979928 147 FKVMLVGESGVGKSTLAGTFGGLQGDSAHEPEnpAEDTYERRIMVDKEEVTLVVYDIWEQGDAGGwLRDHCLQTGDAFLI 226
Cdd:cd04139    1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPT--KADSYRKKVVLDGEEVQLNILDTAGQEDYAA-IRDNYFRSGEGFLL 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 767979928 227 VFSVTDRRSFSKVPEtlLRLRAGRPHHD--LPVILVGNKSDLARSRERA 273
Cdd:cd04139   78 VFSITDMESFTALAE--FREQILRVKEDdnVPLLLVGNKCDLEDKRQVS 124

Ras subfamily of RAS small GTPases; Similar in fold and function to the bacterial EF-Tu GTPase. p21Ras couples receptor Tyr kinases and G protein receptors to protein kinase cascades

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928   147 FKVMLVGESGVGKSTLAGTFggLQG--DSAHEPEnpAEDTYERRIMVDKEEVTLVVYDIweqgdAG----GWLRDHCLQT 220
Cdd:smart00173   1 YKLVVLGSGGVGKSALTIQF--IQGhfVDDYDPT--IEDSYRKQIEIDGEVCLLDILDT-----AGqeefSAMRDQYMRT 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 767979928   221 GDAFLIVFSVTDRRSF---SKVPETLLRLRaGRphHDLPVILVGNKSDLARSRE 271
Cdd:smart00173  72 GEGFLLVYSITDRQSFeeiKKFREQILRVK-DR--DDVPIVLVGNKCDLESERV 122

R-Ras2/TC21, M-Ras/R-Ras3; The M-Ras/R-Ras-like subfamily contains R-Ras2/TC21, M-Ras/R-Ras3, and related members of the Ras family. M-Ras is expressed in lympho-hematopoetic cells. It interacts with some of the known Ras effectors, but appears to also have its own effectors. Expression of mutated M-Ras leads to transformation of several types of cell lines, including hematopoietic cells, mammary epithelial cells, and fibroblasts. Overexpression of M-Ras is observed in carcinomas from breast, uterus, thyroid, stomach, colon, kidney, lung, and rectum. In addition, expression of a constitutively active M-Ras mutant in murine bone marrow induces a malignant mast cell leukemia that is distinct from the monocytic leukemia induced by H-Ras. TC21, along with H-Ras, has been shown to regulate the branching morphogenesis of ureteric bud cell branching in mice. 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 767979928 147 FKVMLVGESGVGKSTLAGTFGGLQGDSAHEPEnpAEDTYERRIMVDKEEVTLVVYDIWEQGDAGGwLRDHCLQTGDAFLI 226
Cdd:cd04145    3 YKLVVVGGGGVGKSALTIQFIQSYFVTDYDPT--IEDSYTKQCEIDGQWARLDILDTAGQEEFSA-MREQYMRTGEGFLL 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 767979928 227 VFSVTDRRSFSKVP---ETLLRLragRPHHDLPVILVGNKSDLARSR 270
Cdd:cd04145   80 VFSVTDRGSFEEVDkfhTQILRV---KDRDEFPMILVGNKADLEHQR 123

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 767979928 147 FKVMLVGESGVGKSTLagTFGGLQGDSAHEPENPAEDTYERRIMVDKEEVTLVVYDIWEQGDAGGwLRDHCLQTGDAFLI 226
Cdd:cd04138    2 YKLVVVGAGGVGKSAL--TIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSA-MRDQYMRTGEGFLC 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767979928 227 VFSVTDRRSFSKVP---ETLLRLragRPHHDLPVILVGNKSDLA 267
Cdd:cd04138   79 VFAINSRKSFEDIHtyrEQIKRV---KDSDDVPMVLVGNKCDLA 119

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 767979928 147 FKVMLVGESGVGKSTLAGTFggLQGDSAHEPENPAEDTYERRIMVDKEEVTLVVYDI--WEQGDAggwLRDHCLQTGDAF 224
Cdd:cd04136    2 YKLVVLGSGGVGKSALTVQF--VQGIFVDKYDPTIEDSYRKQIEVDCQQCMLEILDTagTEQFTA---MRDLYIKNGQGF 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767979928 225 LIVFSVTDRRSFSKVP---ETLLRLRAgrpHHDLPVILVGNKSDLARSRE 271
Cdd:cd04136   77 ALVYSITAQQSFNDLQdlrEQILRVKD---TEDVPMILVGNKCDLEDERV 123

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 767979928 147 FKVMLVGESGVGKSTLAGTFggLQGDSAHEPENPAEDTYERRIMVDKEEVTLVVYDIwEQGDAGGWLRDHCLQTGDAFLI 226
Cdd:cd04140    2 YRVVVFGAGGVGKSSLVLRF--VKGTFRESYIPTIEDTYRQVISCSKSICTLQITDT-TGSHQFPAMQRLSISKGHAFIL 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 767979928 227 VFSVTDRRSFSKVPE--TLLRLRAGRPHHDLPVILVGNKSDLARSRE 271
Cdd:cd04140   79 VYSITSKQSLEELKPiyELICEIKGNNLEKIPIMLVGNKCDESPSRE 125

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 767979928 147 FKVMLVGESGVGKSTLAGTFggLQGDSAHEPENPAEDTYERRIMVDKEEVTLVVYDI--WEQGDAggwLRDHCLQTGDAF 224
Cdd:cd04176    2 YKVVVLGSGGVGKSALTVQF--VSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTagTEQFAS---MRDLYIKNGQGF 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767979928 225 LIVFSVTDRRSFSKVP---ETLLRLRAGRPhhdLPVILVGNKSDLARSRE 271
Cdd:cd04176   77 IVVYSLVNQQTFQDIKpmrDQIVRVKGYEK---VPIILVGNKVDLESERE 123

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 767979928  148 KVMLVGESGVGKSTLAGTFgglQGDSAHEPENP--AEDTYERRIMVDKEEVTLVVYDIWeqgDAGGW-----LRDHCLQT 220
Cdd:pfam08477   1 KVVLLGDSGVGKTSLLKRF---VDDTFDPKYKStiGVDFKTKTVLENDDNGKKIKLNIW---DTAGQerfrsLHPFYYRG 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 767979928  221 GDAFLIVFsvtDRRSFSKVPETLLRLRAGRPhhDLPVILVGNKSD 265
Cdd:pfam08477  75 AAAALLVY---DSRTFSNLKYWLRELKKYAG--NSPVILVGNKID 114

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 767979928 147 FKVMLVGESGVGKSTLA-----GTFgglqgdsaHEPENP--AEDTYERRIMVDKEEVTLvvyDIWeqgDAGGWLRDHCLQ 219
Cdd:cd00154    1 FKIVLIGDSGVGKTSLLlrfvdNKF--------SENYKStiGVDFKSKTIEVDGKKVKL---QIW---DTAGQERFRSIT 66

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 767979928 220 TG-----DAFLIVFSVTDRRSFSKVPETLLRLRA-GRPhhDLPVILVGNKSDLARSRE 271
Cdd:cd00154   67 SSyyrgaHGAILVYDVTNRESFENLDKWLNELKEyAPP--NIPIILVGNKSDLEDERQ 122

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 767979928 148 KVMLVGESGVGKSTL-----AGTFgglqgdsahepenPAE------DTYERRIMVDKEEVTLVVYDIWEQGDAGGwLRDH 216
Cdd:cd00157    2 KIVVVGDGAVGKTCLlisytTNKF-------------PTEyvptvfDNYSANVTVDGKQVNLGLWDTAGQEEYDR-LRPL 67

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 767979928 217 CLQTGDAFLIVFSVTDRRSFSKV-----PEtlLRlragrpHH--DLPVILVGNKSDL 266
Cdd:cd00157   68 SYPQTDVFLLCFSVDSPSSFENVktkwyPE--IK------HYcpNVPIILVGTKIDL 116

Wnt-1 responsive Cdc42 homolog (Wrch-1) is a Rho family GTPase similar to Cdc42; Wrch-1 (Wnt-1 responsive Cdc42 homolog) is a Rho family GTPase that shares significant sequence and functional similarity with Cdc42. Wrch-1 was first identified in mouse mammary epithelial cells, where its transcription is upregulated in Wnt-1 transformation. Wrch-1 contains N- and C-terminal extensions relative to cdc42, suggesting potential differences in cellular localization and function. The Wrch-1 N-terminal extension contains putative SH3 domain-binding motifs and has been shown to bind the SH3 domain-containing protein Grb2, which increases the level of active Wrch-1 in cells. Unlike Cdc42, which localizes to the cytosol and perinuclear membranes, Wrch-1 localizes extensively with the plasma membrane and endosomes. The membrane association, localization, and biological activity of Wrch-1 indicate an atypical model of regulation distinct from other Rho family GTPases. 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. 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 767979928 148 KVMLVGESGVGKSTL--AGTFGGLQgdsaHEPENPAEDTYERRIMVDKEEVTLVVYDIWEQGDAGGwLRDHCLQTGDAFL 225
Cdd:cd04130    2 KCVLVGDGAVGKTSLivSYTTNGYP----TEYVPTAFDNFSVVVLVDGKPVRLQLCDTAGQDEFDK-LRPLCYPDTDVFL 76

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767979928 226 IVFSVTDRRSFSKVPETLL-RLRAGRPHhdLPVILVGNKSDL----------ARSRERAAT 275
Cdd:cd04130   77 LCFSVVNPSSFQNISEKWIpEIRKHNPK--APIILVGTQADLrtdvnvliqlARYGEKPVS 135

Rab-related GTPase family includes Rab5 and Rab22; regulates early endosome fusion; The Rab5-related subfamily includes Rab5 and Rab22 of mammals, Ypt51/Ypt52/Ypt53 of yeast, and RabF of plants. The members of this subfamily are involved in endocytosis and endocytic-sorting pathways. In mammals, Rab5 GTPases localize to early endosomes and regulate fusion of clathrin-coated vesicles to early endosomes and fusion between early endosomes. In yeast, Ypt51p family members similarly regulate membrane trafficking through prevacuolar compartments. 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 767979928 147 FKVMLVGESGVGKSTLAGTFgglQGDSAHEPENP----AEDTYerRIMVDKEEVTLvvyDIWeqgDAGGWLRDHCL---- 218
Cdd:cd01860    2 FKLVLLGDSSVGKSSIVLRF---VKNEFSENQEStigaAFLTQ--TVNLDDTTVKF---EIW---DTAGQERYRSLapmy 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 767979928 219 -QTGDAFLIVFSVTDRRSFSKVPETLLRLRAGRPhHDLPVILVGNKSDLARSRE 271
Cdd:cd01860   71 yRGAAAAIVVYDITSEESFEKAKSWVKELQEHGP-PNIVIALAGNKADLESKRQ 123

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928 148 KVMLVGESGVGKSTLAGTFGGLQ-GDSAHEPENPAeDTYERRIMVDKEEVTLVVYDIweqgdAG-------GWLRDHCLQ 219
Cdd:COG1100    5 KIVVVGTGGVGKTSLVNRLVGDIfSLEKYLSTNGV-TIDKKELKLDGLDVDLVIWDT-----PGqdefretRQFYARQLT 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 767979928 220 TGDAFLIVFSVTDRRSFSKVPETLLRL-RAGRphhDLPVILVGNKSDLARSRER 272
Cdd:COG1100   79 GASLYLFVVDGTREETLQSLYELLESLrRLGK---KSPIILVLNKIDLYDEEEI 129

Mitochondrial Rho family 1 (Miro1), N-terminal; Miro1 subfamily. Miro (mitochondrial Rho) proteins have tandem GTP-binding domains separated by a linker region containing putative calcium-binding EF hand motifs. Genes encoding Miro-like proteins were found in several eukaryotic organisms. This CD represents the N-terminal GTPase domain of Miro proteins. These atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. Most Rho proteins contain a lipid modification site at the C-terminus; however, Miro is one of few Rho subfamilies that lack this feature.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928 148 KVMLVGESGVGKSTLAGTFggLQGDSahePEN----------PAEDTYERrimvdkeeVTLVVYDIWEQGDAGGWLRDHC 217
Cdd:cd01893    4 RIVLIGDEGVGKSSLIMSL--VSEEF---PENvprvlpeitiPADVTPER--------VPTTIVDTSSRPQDRANLAAEI 70

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 767979928 218 lQTGDAFLIVFSVTDRRSFSKVPE---TLLRLRAGRphhdLPVILVGNKSDL 266
Cdd:cd01893   71 -RKANVICLVYSVDRPSTLERIRTkwlPLIRRLGVK----VPIILVGNKSDL 117

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 767979928 147 FKVMLVGESGVGKSTLAGTFggLQGDSAhEPENP--AEDTYERriMVDKEEVTLVVYDIWeqgDAGGWLRDHCLQTGD-- 222
Cdd:cd04111    3 FRLIVIGDSTVGKSSLLKRF--TEGRFA-EVSDPtvGVDFFSR--LIEIEPGVRIKLQLW---DTAGQERFRSITRSYyr 74

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 767979928 223 ---AFLIVFSVTDRRSFSKVPETLLRLRAG-RPHHdlPV-ILVGNKSDLARSRE 271
Cdd:cd04111   75 nsvGVLLVFDITNRESFEHVHDWLEEARSHiQPHR--PVfILVGHKCDLESQRQ 126

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 767979928 147 FKVMLVGESGVGKSTLAGTFGGLQGDSAHEPENPAeDTYERRIMVDKEEVTLvvyDIWeqgDAGGWLRDHCLqtGDAF-- 224
Cdd:cd01862    1 LKVIILGDSGVGKTSLMNQYVNKKFSNQYKATIGA-DFLTKEVTVDDRLVTL---QIW---DTAGQERFQSL--GVAFyr 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767979928 225 -----LIVFSVTDRRSFSKV----PETLLRLRAGRPHHdLPVILVGNKSDLARSR----ERAATW 276
Cdd:cd01862   72 gadccVLVYDVTNPKSFESLdswrDEFLIQASPRDPEN-FPFVVLGNKIDLEEKRqvstKKAQQW 135

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 767979928 147 FKVMLVGESGVGKSTLAGTFGGLQGDSAHEPEnpAEDtYERRIMVDKEEVTLVvyDIWeqgDAGGW-----LRDHCLQTG 221
Cdd:cd04143    1 YRMVVLGASKVGKTAIVSRFLGGRFEEQYTPT--IED-FHRKLYSIRGEVYQL--DIL---DTSGNhpfpaMRRLSILTG 72

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 767979928 222 DAFLIVFSVTDRRSFSKVPETLLRLRAG--------RPHHDLPVILVGNKSDLARSRE 271
Cdd:cd04143   73 DVFILVFSLDNRESFEEVCRLREQILETksclknktKENVKIPMVICGNKADRDFPRE 130

GTP-binding nuclear protein Ran; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767979928 147 FKVMLVGESGVGKST-----LAGTFgglqgdsahepenpaEDTYERRIMVDKEEVTL------VVYDIWE---QGDAGGw 212
Cdd:PLN03071  14 FKLVIVGDGGTGKTTfvkrhLTGEF---------------EKKYEPTIGVEVHPLDFftncgkIRFYCWDtagQEKFGG- 77

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 767979928 213 LRDHCLQTGDAFLIVFSVTDRRSFSKVPETLLRLRagRPHHDLPVILVGNKSDLaRSRE 271
Cdd:PLN03071  78 LRDGYYIHGQCAIIMFDVTARLTYKNVPTWHRDLC--RVCENIPIVLCGNKVDV-KNRQ 133

Rab GTPase family 19 (Rab19); Rab19 subfamily. Rab19 proteins are associated with Golgi stacks. Similarity analysis indicated that Rab41 is closely related to Rab19. However, the function of these Rabs is not yet characterized. 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 767979928 144 DGIFKVMLVGESGVGKSTL-----AGTFGGLQGDSAhepenpAEDTYERRIMVDKEEVTLvvyDIWeqgDAGGWLRDHCL 218
Cdd:cd01864    1 DFLFKIILIGDSNVGKTCVvqrfkSGTFSERQGNTI------GVDFTMKTLEIQGKRVKL---QIW---DTAGQERFRTI 68