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 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDTNFN--FPDMRRLSIASASAFLLVFSV 99
Cdd:cd00876     1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQeeFSAMRDQYIRNGDGFILVYSI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 100 DDVTSFKEMSDIWQEICSRRSDlNELPIVVVGNKCDVENK-KIYEETAKAFTNrlSSDVRYIEVSAKDNIRITDVFRTLL 178
Cdd:cd00876    81 TSRESFEEIKNIREQILRVKDK-EDVPIVLVGNKCDLENErQVSTEEGEALAE--EWGCPFLETSAKTNINIDELFNTLV 157

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 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDTNFN--FPDMRRLSIASASAFLLVFSV 99
Cdd:cd00876     1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQeeFSAMRDQYIRNGDGFILVYSI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 100 DDVTSFKEMSDIWQEICSRRSDlNELPIVVVGNKCDVENK-KIYEETAKAFTNrlSSDVRYIEVSAKDNIRITDVFRTLL 178
Cdd:cd00876    81 TSRESFEEIKNIREQILRVKDK-EDVPIVLVGNKCDLENErQVSTEEGEALAE--EWGCPFLETSAKTNINIDELFNTLV 157

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETI-EDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTIgVDFYTKTIEVDGKTVKLQIWDTagQERFRALRPLYYRGADGFLLVYD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICsRRSDLNeLPIVVVGNKCDVENKK-IYEETAKAFTNRLssDVRYIEVSAKDNIRITDVFRTL 177
Cdd:pfam00071  81 ITSRDSFENVKKWVEEIL-RHADEN-VPIVLVGNKCDLEDQRvVSTEEGEALAKEL--GLPFMETSAKTNENVEEAFEEL 156

                  ...
gi 1767286943 178 LEL 180
Cdd:pfam00071 157 ARE 159

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFS-SKYKETIEDLHSR-EFRIQGVPLPLDILDTnfnfP------DMRRL---SIASA 90
Cdd:COG1100     5 KIVVVGTGGVGKTSLVNRLVGDIFSlEKYLSTNGVTIDKkELKLDGLDVDLVIWDT----PgqdefrETRQFyarQLTGA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  91 SAFLLVFSVDDVTSFKEMSDiWQEICSRRSDLneLPIVVVGNKCD-VENKKIYEETAKAFTNRLSSDVRYIEVSAKDNIR 169
Cdd:COG1100    81 SLYLFVVDGTREETLQSLYE-LLESLRRLGKK--SPIILVLNKIDlYDEEEIEDEERLKEALSEDNIVEVVATSAKTGEG 157

                         170
                  ....*....|
gi 1767286943 170 ITDVFRTLLE 179
Cdd:COG1100   158 VEELFAALAE 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 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDTNFN--FPDMRRLSIASASAFLLVFSV 99
Cdd:cd00876     1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQeeFSAMRDQYIRNGDGFILVYSI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 100 DDVTSFKEMSDIWQEICSRRSDlNELPIVVVGNKCDVENK-KIYEETAKAFTNrlSSDVRYIEVSAKDNIRITDVFRTLL 178
Cdd:cd00876    81 TSRESFEEIKNIREQILRVKDK-EDVPIVLVGNKCDLENErQVSTEEGEALAE--EWGCPFLETSAKTNINIDELFNTLV 157

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 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04143     1 YRMVVLGASKVGKTAIVSRFLGGRFEEQYTPTIEDFHRKLYSIRGEVYQLDILDTsgNHPFPAMRRLSILTGDVFILVFS 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICSRRS-------DLNELPIVVVGNKCDVENKKiyEETAKAFTNRLSSDVR--YIEVSAKDNIR 169
Cdd:cd04143    81 LDNRESFEEVCRLREQILETKSclknktkENVKIPMVICGNKADRDFPR--EVQRDEVEQLVGGDENcaYFEVSAKKNSN 158

                         170
                  ....*....|....*
gi 1767286943 170 ITDVFRTLLELSGFP 184
Cdd:cd04143   159 LDEMFRALFSLAKLP 173

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 1767286943   21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:smart00173   1 YKLVVLGSGGVGKSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTagQEEFSAMRDQYMRTGEGFLLVYS 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943   99 VDDVTSFKEMSDIWQEICsRRSDLNELPIVVVGNKCDVENK-KIYEETAKAFTNRLSsdVRYIEVSAKDNIRITDVFRTL 177
Cdd:smart00173  81 ITDRQSFEEIKKFREQIL-RVKDRDDVPIVLVGNKCDLESErVVSTEEGKELARQWG--CPFLETSAKERVNVDEAFYDL 157

                   .
gi 1767286943  178 L 178
Cdd:smart00173 158 V 158

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 1767286943  19 ERYRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLV 96
Cdd:cd04145     1 PTYKLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTagQEEFSAMREQYMRTGEGFLLV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  97 FSVDDVTSFKEMSDIWQEICsRRSDLNELPIVVVGNKCDVEN-KKIYEETAKAFTNRLSsdVRYIEVSAKDNIRITDVFR 175
Cdd:cd04145    81 FSVTDRGSFEEVDKFHTQIL-RVKDRDEFPMILVGNKADLEHqRQVSREEGQELARQLK--IPYIETSAKDRVNVDKAFH 157

                  ....*
gi 1767286943 176 TLLEL 180
Cdd:cd04145   158 DLVRV 162

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 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04175     2 YKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTagTEQFTAMRDLYMKNGQGFVLVYS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICsRRSDLNELPIVVVGNKCDVENKKIY-EETAKAFTNRLssDVRYIEVSAKDNIRITDVFRTL 177
Cdd:cd04175    82 ITAQSTFNDLQDLREQIL-RVKDTEDVPMILVGNKCDLEDERVVgKEQGQNLARQW--GCAFLETSAKAKINVNEIFYDL 158

                  ..
gi 1767286943 178 LE 179
Cdd:cd04175   159 VR 160

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 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04140     2 YRVVVFGAGGVGKSSLVLRFVKGTFRESYIPTIEDTYRQVISCSKSICTLQITDTtgSHQFPAMQRLSISKGHAFILVYS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICSRRSD-LNELPIVVVGNKCD-VENKKIYEETAKAFTNRLSsdVRYIEVSAKDNIRITDVFRT 176
Cdd:cd04140    82 ITSKQSLEELKPIYELICEIKGNnLEKIPIMLVGNKCDeSPSREVSSSEGAALARTWN--CAFMETSAKTNHNVQELFQE 159

                  ....
gi 1767286943 177 LLEL 180
Cdd:cd04140   160 LLNL 163

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 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04136     2 YKLVVLGSGGVGKSALTVQFVQGIFVDKYDPTIEDSYRKQIEVDCQQCMLEILDTagTEQFTAMRDLYIKNGQGFALVYS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICsRRSDLNELPIVVVGNKCDVENKKIYEETAKAFTNRLSSDVRYIEVSAKDNIRITDVFRTLL 178
Cdd:cd04136    82 ITAQQSFNDLQDLREQIL-RVKDTEDVPMILVGNKCDLEDERVVSKEEGQNLARQWGNCPFLETSAKSKINVDEIFYDLV 160

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 1767286943  20 RYRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVF 97
Cdd:cd04176     1 EYKVVVLGSGGVGKSALTVQFVSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTagTEQFASMRDLYIKNGQGFIVVY 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1767286943  98 SVDDVTSFKEMSDIWQEIcSRRSDLNELPIVVVGNKCDVENKKiyeETAKAFTNRLSS--DVRYIEVSAKDNIRITDVF 174
Cdd:cd04176    81 SLVNQQTFQDIKPMRDQI-VRVKGYEKVPIILVGNKVDLESER---EVSSAEGRALAEewGCPFMETSAKSKTMVNELF 155

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 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFSV 99
Cdd:cd04137     3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPTIENTFSKIITYKGQEYHLEIVDTagQDEYSILPQKYSIGIHGYILVYSV 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 100 DDVTSFKEMSDIWQEICSRRSDLNeLPIVVVGNKCDVENKK-IYEETAKAFTNRLssDVRYIEVSAKDNIRITDVFRTLL 178
Cdd:cd04137    83 TSRKSFEVVKVIYDKILDMLGKES-VPIVLVGNKSDLHMERqVSAEEGKKLAESW--GAAFLESSAKENENVEEAFELLI 159

                  .
gi 1767286943 179 E 179
Cdd:cd04137   160 E 160

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 1767286943  23 LVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFSVD 100
Cdd:cd00157     3 IVVVGDGAVGKTCLLISYTTNKFPTEYVPTVFDNYSANVTVDGKQVNLGLWDTagQEEYDRLRPLSYPQTDVFLLCFSVD 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 101 DVTSFKEMSDIW-QEIcsrRSDLNELPIVVVGNKCDVENKK------------IYEETAKAFTNRLSSdVRYIEVSAKDN 167
Cdd:cd00157    83 SPSSFENVKTKWyPEI---KHYCPNVPIILVGTKIDLRDDGntlkklekkqkpITPEEGEKLAKEIGA-VKYMECSALTQ 158

                  ....*..
gi 1767286943 168 IRITDVF 174
Cdd:cd00157   159 EGLKEVF 165

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 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETI-EDLHSREFRIQGVPLPLDILDT--NFNFpdmRRLSIA---SASAFL 94
Cdd:cd01862     1 LKVIILGDSGVGKTSLMNQYVNKKFSNQYKATIgADFLTKEVTVDDRLVTLQIWDTagQERF---QSLGVAfyrGADCCV 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  95 LVFSVDDVTSFKEMsDIWQE---ICSRRSDLNELPIVVVGNKCDVENK-KIYEETAKAF--TNrlsSDVRYIEVSAKDNI 168
Cdd:cd01862    78 LVYDVTNPKSFESL-DSWRDeflIQASPRDPENFPFVVLGNKIDLEEKrQVSTKKAQQWckSK---GNIPYFETSAKEAI 153

                  ....*....
gi 1767286943 169 RITDVFRTL 177
Cdd:cd01862   154 NVDQAFETI 162

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  21 YRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIED-LHSREFRIQGVPLPLDILDT----NFNF--PDMRRlsiaSASAF 93
Cdd:cd04123     1 FKVVLLGEGRVGKTSLVLRYVENKFNEKHESTTQAsFFQKTVNIGGKRIDLAIWDTagqeRYHAlgPIYYR----DADGA 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  94 LLVFSVDDVTSFKEMSDIWQEICSRRSdlNELPIVVVGNKCDVENKK-IYEETAKAFTNrlSSDVRYIEVSAKDNIRITD 172
Cdd:cd04123    77 ILVYDITDADSFQKVKKWIKELKQMRG--NNISLVIVGNKIDLERQRvVSKSEAEEYAK--SVGAKHFETSAKTGKGIEE 152

                  ....*
gi 1767286943 173 VFRTL 177
Cdd:cd04123   153 LFLSL 157

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 1767286943  23 LVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT----NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04146     2 IAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTpgqqQNEDPESLERSLRWADGFVLVYS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  99 VDDVTSFKEMSDIWQEICSRRSDLNELPIVVVGNKCDVEN-KKIYEETAKAFTNRLSSdvRYIEVSAKDNI-RITDVFRT 176
Cdd:cd04146    82 ITDRSSFDVVSQLLQLIREIKKRDGEIPVILVGNKADLLHsRQVSTEEGQKLALELGC--LFFEVSAAENYlEVQNVFHE 159

                  ...
gi 1767286943 177 LLE 179
Cdd:cd04146   160 LCR 162

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 1767286943  24 VVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFSVDD 101
Cdd:cd04130     4 VLVGDGAVGKTSLIVSYTTNGYPTEYVPTAFDNFSVVVLVDGKPVRLQLCDTagQDEFDKLRPLCYPDTDVFLLCFSVVN 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943 102 VTSFKEMSDIW-QEIcsrRSDLNELPIVVVGNKCDV-------------ENKKIYEETAKAFTNRLSSdVRYIEVSAKDN 167
Cdd:cd04130    84 PSSFQNISEKWiPEI---RKHNPKAPIILVGTQADLrtdvnvliqlaryGEKPVSQSRAKALAEKIGA-CEYIECSALTQ 159

                  ....*....
gi 1767286943 168 IRITDVFRT 176
Cdd:cd04130   160 KNLKEVFDT 168

Rho (Ras homology) subfamily of Ras-like small GTPases; Members of this subfamily of Ras-like small GTPases include Cdc42 and Rac, as well as Rho isoforms.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943   23 LVVLGSAKVGKTNIIRRYLYNEFSSKYKETIEDLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFSVD 100
Cdd:smart00174   1 LVVVGDGAVGKTCLLIVYTTNAFPEDYVPTVFENYSADVEVDGKPVELGLWDTagQEDYDRLRPLSYPDTDVFLICFSVD 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  101 DVTSFKEMSDIWQ-EIcsrRSDLNELPIVVVGNKCDVENKK-------------IYEETAKAFTNRLSSdVRYIEVSAKD 166
Cdd:smart00174  81 SPASFENVKEKWYpEV---KHFCPNVPIILVGTKLDLRNDKstleelskkkqepVTYEQGQALAKRIGA-VKYLECSALT 156

                          170
                   ....*....|
gi 1767286943  167 NIRITDVFRT 176
Cdd:smart00174 157 QEGVREVFEE 166

Rab GTPase family 9 (Rab9); Rab9 is found in late endosomes, together with mannose 6-phosphate receptors (MPRs) and the tail-interacting protein of 47 kD (TIP47). Rab9 is a key mediator of vesicular transport from late endosomes to the trans-Golgi network (TGN) by redirecting the MPRs. Rab9 has been identified as a key component for the replication of several viruses, including HIV1, Ebola, Marburg, and measles, making it a potential target for inhibiting a variety of viruses. 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 1767286943  22 RLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIE-DLHSREFRIQGVPLPLDILDT--NFNFPDMRRLSIASASAFLLVFS 98
Cdd:cd04116     7 KVILLGDGGVGKSSLMNRYVTNKFDTQLFHTIGvEFLNKDLEVDGHFVTLQIWDTagQERFRSLRTPFYRGSDCCLLTFS 86

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1767286943  99 VDDVTSFKEMSdIWQEICSRRSDLNE---LPIVVVGNKCDVENKKIYEETAKAFTnRLSSDVRYIEVSAKDNIRITDVF 174
Cdd:cd04116    87 VDDSQSFQNLS-NWKKEFIYYADVKEpesFPFVILGNKIDIPERQVSTEEAQAWC-RDNGDYPYFETSAKDATNVAAAF 163

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 1767286943  20 RYRLVVLGSAKVGKTNIIRRYLYNEFSSKYKETIedlhSREFRIQGVPLP-----LDILDT----NFNfpdmrrlSIAS- 89
Cdd:cd01860     1 QFKLVLLGDSSVGKSSIVLRFVKNEFSENQESTI----GAAFLTQTVNLDdttvkFEIWDTagqeRYR-------SLAPm 69

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1767286943  90 ----ASAFLLVFSVDDVTSFKEMSDIWQEIcsRRSDLNELPIVVVGNKCDVENK-KIYEETAKAFTNRLSSDvrYIEVSA 164
Cdd:cd01860    70 yyrgAAAAIVVYDITSEESFEKAKSWVKEL--QEHGPPNIVIALAGNKADLESKrQVSTEEAQEYADENGLL--FMETSA 145

                         170
                  ....*....|
gi 1767286943 165 KDNIRITDVF 174
Cdd:cd01860   146 KTGENVNELF 155