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 14249704      6 EVKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVY 84
Cdd:smart00010   2 EYKLVVLGGGGVGKSALTIQFVQGHFVDEYDPTIEDSYRKQIEIDGEVCLLDILDTAGQEEfSAMRDQYMRTGEGFLLVY 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704     85 DITDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELC 164
Cdd:smart00010  82 SITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKERI-NVDEAFYDLV 160

                   ....*.
gi 14249704    165 REVRRR 170
Cdd:smart00010 161 REIRKS 166

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704    4 SAEVKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVL 82
Cdd:PTZ00369   3 STEYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTIEDSYRKQCVIDEETCLLDILDTAGQEEySAMRDQYMRTGQGFLC 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   83 VYDITDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSAcTGEGNITEIFYE 162
Cdd:PTZ00369  83 VYSITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDLDSERQVSTGEGQELAKSFGIPFLETSA-KQRVNVDEAFYE 161

                 ....*..
gi 14249704  163 LCREVRR 169
Cdd:PTZ00369 162 LVREIRK 168

small GTP-binding protein domain; Proteins with a small GTP-binding domain recognized by this model include Ras, RhoA, Rab11, translation elongation factor G, translation initiation factor IF-2, tetratcycline resistance protein TetM, CDC42, Era, ADP-ribosylation factors, tdhF, and many others. In some proteins the domain occurs more than once.This model recognizes a large number of small GTP-binding proteins and related domains in larger proteins. Note that the alpha chains of heterotrimeric G proteins are larger proteins in which the NKXD motif is separated from the GxxxxGK[ST] motif (P-loop) by a long insert and are not easily detected by this model. [Unknown function, General]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704     6 EVKLAIFGRAGVGKSALVVRFL-TKRFIWEYDPTLESTYR-HQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVL 82
Cdd:TIGR00231   1 DIKIVIVGHPNVGKSTLLNSLLgNKGSITEYYPGTTRNYVtTVIEEDGKTYKFNLLDTAGQEDyDAIRRLYYPQVERSLR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704    83 VYDITDRG-SFEEVLP--LKNILDEikKPKNVTLILVGNKADLDHsRQVSTEEGEKLATELACAFYECSACTGEgNITEI 159
Cdd:TIGR00231  81 VFDIVILVlDVEEILEkqTKEIIHH--ADSGVPIILVGNKIDLKD-ADLKTHVASEFAKLNGEPIIPLSAETGK-NIDSA 156

                  ....
gi 14249704   160 FYEL 163
Cdd:TIGR00231 157 FKIV 160

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 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVYDI 86
Cdd:cd00876   1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQEEfSAMRDQYIRNGDGFILVYSI 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  87 TDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELCRE 166
Cdd:cd00876  81 TSRESFEEIKNIREQILRVKDKEDVPIVLVGNKCDLENERQVSTEEGEALAEEWGCPFLETSAKTNI-NIDELFNTLVRE 159

                .
gi 14249704 167 V 167
Cdd:cd00876 160 I 160

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 14249704      8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVYDI 86
Cdd:smart00173   2 KLVVLGSGGVGKSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTAGQEEfSAMRDQYMRTGEGFLLVYSI 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704     87 TDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELCRE 166
Cdd:smart00173  82 TDRQSFEEIKKFREQILRVKDRDDVPIVLVGNKCDLESERVVSTEEGKELARQWGCPFLETSAKERV-NVDEAFYDLVRE 160

                   ....
gi 14249704    167 VRRR 170
Cdd:smart00173 161 IRKK 164

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 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVYDI 86
Cdd:cd04145   4 KLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAGQEEfSAMREQYMRTGEGFLLVFSV 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  87 TDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSAcTGEGNITEIFYELCRE 166
Cdd:cd04145  84 TDRGSFEEVDKFHTQILRVKDRDEFPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETSA-KDRVNVDKAFHDLVRV 162

                ..
gi 14249704 167 VR 168
Cdd:cd04145 163 IR 164

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 14249704   6 EVKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVY 84
Cdd:cd04175   1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAGTEQfTAMRDLYMKNGQGFVLVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  85 DITDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSAcTGEGNITEIFYELC 164
Cdd:cd04175  81 SITAQSTFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSA-KAKINVNEIFYDLV 159

                ....*
gi 14249704 165 REVRR 169
Cdd:cd04175 160 RQINR 164

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 14249704   6 EVKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVY 84
Cdd:cd04138   1 EYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEySAMRDQYMRTGEGFLCVF 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  85 DITDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDhSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELC 164
Cdd:cd04138  81 AINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDLA-ARTVSTRQGQDLAKSYGIPYIETSAKTRQ-GVEEAFYTLV 158

                ....
gi 14249704 165 REVR 168
Cdd:cd04138 159 REIR 162

Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases); The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVYDI 86
Cdd:cd04144   1 KLVVLGDGGVGKTALTIQLCLNHFVETYDPTIEDSYRKQVVVDGQPCMLEVLDTAGQEEyTALRDQWIREGEGFILVYSI 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  87 TDRGSFEEVLPLKNILDEIKK--PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELC 164
Cdd:cd04144  81 TSRSTFERVERFREQIQRVKDesAADVPIMIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNV-NVERAFYTLV 159

                       170       180
                ....*....|....*....|....
gi 14249704 165 REVRRRRmvQGKTRRRSSTTHVKQ 188
Cdd:cd04144 160 RALRQQR--QGGQGPKGGPTKKKE 181

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 14249704   6 EVKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQED-TIQREGHMRWGEGFVLVY 84
Cdd:cd04136   1 EYKLVVLGSGGVGKSALTVQFVQGIFVDKYDPTIEDSYRKQIEVDCQQCMLEILDTAGTEQfTAMRDLYIKNGQGFALVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  85 DITDRGSFEEVLPLKNILDEIKKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELA-CAFYECSACTgEGNITEIFYEL 163
Cdd:cd04136  81 SITAQQSFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVSKEEGQNLARQWGnCPFLETSAKS-KINVDEIFYDL 159

                ....
gi 14249704 164 CREV 167
Cdd:cd04136 160 VRQI 163

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 14249704   7 VKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYR-HQATIDDEVVSMEILDTAGQE--DTIQREgHMRWGEGFVLV 83
Cdd:cd00154   1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTIGVDFKsKTIEVDGKKVKLQIWDTAGQErfRSITSS-YYRGAHGAILV 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  84 YDITDRGSFEEVlplKNILDEIKK--PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFY 161
Cdd:cd00154  80 YDVTNRESFENL---DKWLNELKEyaPPNIPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGE-NVDEAFE 155

                ....
gi 14249704 162 ELCR 165
Cdd:cd00154 156 SLAR 159

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 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQ-EDTIQREGHMRWGEGFVLVYDI 86
Cdd:cd04137   3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPTIENTFSKIITYKGQEYHLEIVDTAGQdEYSILPQKYSIGIHGYILVYSV 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  87 TDRGSFE--EVLPLKnILDEIKKpKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYELC 164
Cdd:cd04137  83 TSRKSFEvvKVIYDK-ILDMLGK-ESVPIVLVGNKSDLHMERQVSAEEGKKLAESWGAAFLESSAKENE-NVEEAFELLI 159

                ....*
gi 14249704 165 REVRR 169
Cdd:cd04137 160 EEIEK 164

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 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAG--QEDTIQREGHMRwGEGFVLVYD 85
Cdd:cd04140   3 RVVVFGAGGVGKSSLVLRFVKGTFRESYIPTIEDTYRQVISCSKSICTLQITDTTGshQFPAMQRLSISK-GHAFILVYS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  86 ITDRGSFEEVLPLKNILDEIK--KPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYEL 163
Cdd:cd04140  82 ITSKQSLEELKPIYELICEIKgnNLEKIPIMLVGNKCDESPSREVSSSEGAALARTWNCAFMETSAKTNH-NVQELFQEL 160

Rab GTPase families 8, 10, 13 (Rab8, Rab10, Rab13); Rab8/Sec4/Ypt2 are known or suspected to be involved in post-Golgi transport to the plasma membrane. It is likely that these Rabs have functions that are specific to the mammalian lineage and have no orthologs in plants. Rab8 modulates polarized membrane transport through reorganization of actin and microtubules, induces the formation of new surface extensions, and has an important role in directed membrane transport to cell surfaces. The Ypt2 gene of the fission yeast Schizosaccharomyces pombe encodes a member of the Ypt/Rab family of small GTP-binding proteins, related in sequence to Sec4p of Saccharomyces cerevisiae but closer to mammalian Rab8. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQAT-IDDEVVSMEILDTAGQE--DTIQrEGHMRWGEGFVLVY 84
Cdd:cd01867   5 KLLLIGDSGVGKSCLLLRFSEDSFNPSFISTIGIDFKIRTIeLDGKKIKLQIWDTAGQErfRTIT-TSYYRGAMGIILVY 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  85 DITDRGSFEEVlplKNILDEIKK--PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYE 162
Cdd:cd01867  84 DITDEKSFENI---KNWMRNIDEhaSEDVERMLVGNKCDMEEKRVVSKEEGEALAREYGIKFLETSAKANI-NVEEAFLT 159

                ....*...
gi 14249704 163 LCREVRRR 170
Cdd:cd01867 160 LAKDILKK 167

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   7 VKLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQATIDDEVVSMEILDTAGQEDtiqrEGHMR-----WGEGFV 81
Cdd:cd00157   1 IKIVVVGDGAVGKTCLLISYTTNKFPTEYVPTVFDNYSANVTVDGKQVNLGLWDTAGQEE----YDRLRplsypQTDVFL 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  82 LVYDITDRGSFEevlplkNILD----EIKKPK-NVTLILVGNKADL-----------DHSRQVSTEEGEKLATEL-ACAF 144
Cdd:cd00157  77 LCFSVDSPSSFE------NVKTkwypEIKHYCpNVPIILVGTKIDLrddgntlkkleKKQKPITPEEGEKLAKEIgAVKY 150

                       170       180
                ....*....|....*....|.
gi 14249704 145 YECSACTGEGnITEIFYELCR 165
Cdd:cd00157 151 MECSALTQEG-LKEVFDEAIR 170

Rab GTPase family 1 includes the yeast homolog Ypt1; Rab1/Ypt1 subfamily. Rab1 is found in every eukaryote and is a key regulatory component for the transport of vesicles from the ER to the Golgi apparatus. Studies on mutations of Ypt1, the yeast homolog of Rab1, showed that this protein is necessary for the budding of vesicles of the ER as well as for their transport to, and fusion with, the Golgi apparatus. 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 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTYRHQAT-IDDEVVSMEILDTAGQE--DTIQrEGHMRWGEGFVLVY 84
Cdd:cd01869   4 KLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIeLDGKTVKLQIWDTAGQErfRTIT-SSYYRGAHGIIIVY 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  85 DITDRGSFEEVlplKNILDEIKK--PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYE 162
Cdd:cd01869  83 DVTDQESFNNV---KQWLQEIDRyaSENVNKLLVGNKCDLTDKKVVDYTEAKEFADELGIPFLETSAKNAT-NVEEAFMT 158

                ....*...
gi 14249704 163 LCREVRRR 170
Cdd:cd01869 159 MAREIKKR 166

Rab GTPase family 6 (Rab6); Rab6 is involved in microtubule-dependent transport pathways through the Golgi and from endosomes to the Golgi. Rab6A of mammals is implicated in retrograde transport through the Golgi stack, and is also required for a slow, COPI-independent, retrograde transport pathway from the Golgi to the endoplasmic reticulum (ER). This pathway may allow Golgi residents to be recycled through the ER for scrutiny by ER quality-control systems. Yeast Ypt6p, the homolog of the mammalian Rab6 GTPase, is not essential for cell viability. Ypt6p acts in endosome-to-Golgi, in intra-Golgi retrograde transport, and possibly also in Golgi-to-ER trafficking. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTY-RHQATIDDEVVSMEILDTAGQEdtiqR-----EGHMRWGEGFV 81
Cdd:cd01861   2 KLVFLGDQSVGKTSIITRFMYDTFDNQYQATIGIDFlSKTMYVDDKTVRLQLWDTAGQE----RfrsliPSYIRDSSVAV 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704  82 LVYDITDRGSFEEVLP-LKNILDEikKPKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIF 160
Cdd:cd01861  78 VVYDITNRQSFDNTDKwIDDVRDE--RGNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSAKAGH-NVKQLF 154

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704    8 KLAIFGRAGVGKSALVVRFLTKRFIWEYDPTLESTY-RHQATIDDEVVSMEILDTAGQED--TIQREgHMRWGEGFVLVY 84
Cdd:PLN03108   8 KYIIIGDTGVGKSCLLLQFTDKRFQPVHDLTIGVEFgARMITIDNKPIKLQIWDTAGQESfrSITRS-YYRGAAGALLVY 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14249704   85 DITDRGSFEEvlpLKNILDEIKK--PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSACTGEgNITEIFYE 162
Cdd:PLN03108  87 DITRRETFNH---LASWLEDARQhaNANMTIMLIGNKCDLAHRRAVSTEEGEQFAKEHGLIFMEASAKTAQ-NVEEAFIK 162

                 ....*...
gi 14249704  163 LCREVRRR 170
Cdd:PLN03108 163 TAAKIYKK 170