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 530405957  22 NLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVY 98
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957  99 SVDSRQSFDSSSSYLELLALHAKeTQRSIPALLLGNKLDMAQYR 142
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIKK-RDGEIPVILVGNKADLLHSR 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 530405957  22 NLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVY 98
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957  99 SVDSRQSFDSSSSYLELLALHAKeTQRSIPALLLGNKLDMAQYR 142
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIKK-RDGEIPVILVGNKADLLHSR 123

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530405957  17 APLEVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHA 93
Cdd:PTZ00369   2 ASTEYKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTIEDSYRKQCVIDEETCLLDILDTAgqeEYSAMR--DQYMRTGQG 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 530405957  94 FLVVYSVDSRQSFDSSSSYLELLaLHAKETQRsIPALLLGNKLDMAQYR 142
Cdd:PTZ00369  80 FLCVYSITSRSSFEEIASFREQI-LRVKDKDR-VPMILVGNKCDLDSER 126

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 530405957   20 EVNLAILGRRGAGKSALTVKFL-TKRFISEYDPNLEDTYSSE-ETVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLV 96
Cdd:TIGR00231   1 DIKIVIVGHPNVGKSTLLNSLLgNKGSITEYYPGTTRNYVTTvIEEDGKTYKFNLLDTAGQEDYDAIRRlYYPQVERSLR 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 530405957   97 VYSVDSRQSFDS--SSSYLELLALHAKetqRSIPALLLGNKLD 137
Cdd:TIGR00231  81 VFDIVILVLDVEeiLEKQTKEIIHHAD---SGVPIILVGNKID 120

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 530405957  22 NLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVY 98
Cdd:cd04146    1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957  99 SVDSRQSFDSSSSYLELLALHAKeTQRSIPALLLGNKLDMAQYR 142
Cdd:cd04146   81 SITDRSSFDVVSQLLQLIREIKK-RDGEIPVILVGNKADLLHSR 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 530405957    23 LAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYS 99
Cdd:smart00010   5 LVVLGGGGVGKSALTIQFVQGHFVDEYDPTIEDSYRKQIEIDGEVCLLDILDTAgqeEFSAMR--DQYMRTGEGFLLVYS 82

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 530405957   100 VDSRQSFDSSSSYLELLaLHAKETQrSIPALLLGNKLDMAQYR 142
Cdd:smart00010  83 ITDRQSFEEIAKFREQI-LRVKDRD-DVPIVLVGNKCDLENER 123

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 530405957  23 LAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYS 99
Cdd:cd04145    5 LVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAgqeEFSAMR--EQYMRTGEGFLLVFS 82

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957 100 V-DSRQSFDSSSSYLELLALHAKETqrsIPALLLGNKLDMAQYR 142
Cdd:cd04145   83 VtDRGSFEEVDKFHTQILRVKDRDE---FPMILVGNKADLEHQR 123

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 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLDTPRNC-ERYLNWAHAFLVVY 98
Cdd:cd04136    1 EYKLVVLGSGGVGKSALTVQFVQGIFVDKYDPTIEDSYRKQIEVDCQQCMLEILDTAGTEQFTAMrDLYIKNGQGFALVY 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530405957  99 SVDSRQSFDSSSSYLELLaLHAKETQRsIPALLLGNKLDMAQYRI 143
Cdd:cd04136   81 SITAQQSFNDLQDLREQI-LRVKDTED-VPMILVGNKCDLEDERV 123

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 530405957   23 LAILGRRGAGKSALTVKFLTKRFISEYDPNL-EDTYSSEETVDHQPVHLRVMDTADLdtprncER--------YLNwAHA 93
Cdd:pfam00071   2 LVLVGDGGVGKSSLLIRFTQNKFPEEYIPTIgVDFYTKTIEVDGKTVKLQIWDTAGQ------ERfralrplyYRG-ADG 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 530405957   94 FLVVYSVDSRQSFDSSSSYLELLALHAKEtqrSIPALLLGNKLDMAQYR 142
Cdd:pfam00071  75 FLLVYDITSRDSFENVKKWVEEILRHADE---NVPIVLVGNKCDLEDQR 120

RSR1/Bud1p family GTPase; RSR1/Bud1p is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, RSR1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with RSR1 in vivo. In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, RSR1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton. 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 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRncERYLNWAHAFLV 96
Cdd:cd04177    1 DYKIVVLGAGGVGKSALTVQFVQNVFIESYDPTIEDSYRKQVEIDGRQCDLEILDTAGTEqftAMR--ELYIKSGQGFLL 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 530405957  97 VYSVDSRQSFDssssylELLALHA-----KETQRsIPALLLGNKLDMAQYR 142
Cdd:cd04177   79 VYSVTSEASLN------ELGELREqvlriKDSDN-VPMVLVGNKADLEDDR 122

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 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---------DLdtprncerYLNW 90
Cdd:cd04175    1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAgteqftamrDL--------YMKN 72

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 530405957  91 AHAFLVVYSVDSRQSFDSSSSYLELLaLHAKETQrSIPALLLGNKLDMAQYRI 143
Cdd:cd04175   73 GQGFVLVYSITAQSTFNDLQDLREQI-LRVKDTE-DVPMILVGNKCDLEDERV 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 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLV 96
Cdd:cd04138    1 EYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAgqeEYSAMR--DQYMRTGEGFLC 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 530405957  97 VYSVDSRQSFDSSSSYLELLaLHAKETQrSIPALLLGNKLDMAQYRIPFR 146
Cdd:cd04138   79 VFAINSRKSFEDIHTYREQI-KRVKDSD-DVPMVLVGNKCDLAARTVSTR 126

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 530405957  23 LAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLDTPRNCERY-LNWAHAFLVVYSVD 101
Cdd:cd04140    4 VVVFGAGGVGKSSLVLRFVKGTFRESYIPTIEDTYRQVISCSKSICTLQITDTTGSHQFPAMQRLsISKGHAFILVYSIT 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 530405957 102 SRQSFDSSSSYLELLALHAKETQRSIPALLLGNKLDMAQYR 142
Cdd:cd04140   84 SKQSLEELKPIYELICEIKGNNLEKIPIMLVGNKCDESPSR 124

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 530405957  21 VNLAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRNCeRYLNwAHAFLVV 97
Cdd:cd00157    1 IKIVVVGDGAVGKTCLLISYTTNKFPTEYVPTVFDNYSANVTVDGKQVNLGLWDTAgqeEYDRLRPL-SYPQ-TDVFLLC 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 530405957  98 YSVDSRQSFDSSSS--YLELlalhaKETQRSIPALLLGNKLDM 138
Cdd:cd00157   79 FSVDSPSSFENVKTkwYPEI-----KHYCPNVPIILVGTKIDL 116

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 530405957   20 EVNLAILGRRGAGKSALTVKFL-TKRFISEYDPNLEDTYSSE-ETVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLV 96
Cdd:TIGR00231   1 DIKIVIVGHPNVGKSTLLNSLLgNKGSITEYYPGTTRNYVTTvIEEDGKTYKFNLLDTAGQEDYDAIRRlYYPQVERSLR 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 530405957   97 VYSVDSRQSFDS--SSSYLELLALHAKetqRSIPALLLGNKLD 137
Cdd:TIGR00231  81 VFDIVILVLDVEeiLEKQTKEIIHHAD---SGVPIILVGNKID 120

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530405957  24 AILGRRGAGKSALtVKFLTKRFISEYDPNLEDTYSSEE---TVDHQPVHLRVMDTADLD------TPRNCERYLNWAHAF 94
Cdd:cd00882    1 VVVGRGGVGKSSL-LNALLGGEVGEVSDVPGTTRDPDVyvkELDKGKVKLVLVDTPGLDefgglgREELARLLLRGADLI 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957  95 LVVYSVDsRQSFDSSSSYLELLALHAKEtqrsIPALLLGNKLDM 138
Cdd:cd00882   80 LLVVDST-DRESEEDAKLLILRRLRKEG----IPIILVGNKIDL 118

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 530405957  25 ILGRRGAGKSALTVKFLTKRFISEYDPNL-EDTYSSEETVDHQPVHLRVMDTADldtprnCER-------YLNWAHAFLV 96
Cdd:cd00154    5 LIGDSGVGKTSLLLRFVDNKFSENYKSTIgVDFKSKTIEVDGKKVKLQIWDTAG------QERfrsitssYYRGAHGAIL 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 530405957  97 VYSVDSRQSFDSSSSYLELLALHAKEtqrSIPALLLGNKLDMAQYR 142
Cdd:cd00154   79 VYDVTNRESFENLDKWLNELKEYAPP---NIPIILVGNKSDLEDER 121

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 530405957    23 LAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRNceryLNW--AHAFLVV 97
Cdd:smart00174   1 LVVVGDGAVGKTCLLIVYTTNAFPEDYVPTVFENYSADVEVDGKPVELGLWDTAgqeDYDRLRP----LSYpdTDVFLIC 76

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 530405957    98 YSVDSRQSFDSSSS--YLELlalhaKETQRSIPALLLGNKLDM 138
Cdd:smart00174  77 FSVDSPASFENVKEkwYPEV-----KHFCPNVPIILVGTKLDL 114

Rab GTPase family 2 (Rab2); Rab2 is localized on cis-Golgi membranes and interacts with Golgi matrix proteins. Rab2 is also implicated in the maturation of vesicular tubular clusters (VTCs), which are microtubule-associated intermediates in transport between the ER and Golgi apparatus. In plants, Rab2 regulates vesicle trafficking between the ER and the Golgi bodies and is important to pollen tube growth. 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 530405957  25 ILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEE-TVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVYSVDS 102
Cdd:cd01866    9 IIGDTGVGKSCLLLQFTDKRFQPVHDLTIGVEFGARMiTIDGKQIKLQIWDTAGQESFRSITRsYYRGAAGALLVYDITR 88

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 530405957 103 RQSFDSSSSYLELLALHAKETqrsIPALLLGNKLDMAQYR 142
Cdd:cd01866   89 RETFNHLTSWLEDARQHSNSN---MTIMLIGNKCDLESRR 125

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 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRFISEYDPNLED-TYSSEETVDHQPVHLrvMDTA----DLDTPRNCERYlnwAHAF 94
Cdd:cd01893    2 DVRIVLIGDEGVGKSSLIMSLVSEEFPENVPRVLPEiTIPADVTPERVPTTI--VDTSsrpqDRANLAAEIRK---ANVI 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530405957  95 LVVYSVDSRQSFDSSSSY-LELLalhaKETQRSIPALLLGNKLDM 138
Cdd:cd01893   77 CLVYSVDRPSTLERIRTKwLPLI----RRLGVKVPIILVGNKSDL 117

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 530405957  25 ILGRRGAGKSALTVKFLTKRFISEYDPNL-EDTYSSEETVDHQPVHLRVMDTAdldtprNCERYLNWAHAF-------LV 96
Cdd:cd01862    5 ILGDSGVGKTSLMNQYVNKKFSNQYKATIgADFLTKEVTVDDRLVTLQIWDTA------GQERFQSLGVAFyrgadccVL 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 530405957  97 VYSVDSRQSFDSSSSYL-ELLALHAKETQRSIPALLLGNKLDMAQYR 142
Cdd:cd01862   79 VYDVTNPKSFESLDSWRdEFLIQASPRDPENFPFVVLGNKIDLEEKR 125

Rab GTPase family 26 (Rab26); Rab26 subfamily. First identified in rat pancreatic acinar cells, Rab26 is believed to play a role in recruiting mature granules to the plasma membrane upon beta-adrenergic stimulation. Rab26 belongs to the Rab functional group III, which are considered key regulators of intracellular vesicle transport during exocytosis. 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 530405957  25 ILGRRGAGKSALTVK-----FLTKRFISEYDPNLEDTYSseeTVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVY 98
Cdd:cd04112    5 LVGDSGVGKTCLLVRfkdgaFLAGSFIATVGIQFTNKVV---TVDGVKVKLQIWDTAGQERFRSVTHaYYRDAHALLLLY 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530405957  99 SVDSRQSFDSSSSYLELLALHAKETQRsipALLLGNKLDMAQYRI 143
Cdd:cd04112   82 DVTNKSSFDNIRAWLTEILEYAQSDVV---IMLLGNKADMSGERV 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 530405957   23 LAILGRRGAGKSALTVKFLTKRFISEYDPNLEDTYSSEETVDHQP----VHLRVMDTADLdtprncER-------YLNWA 91
Cdd:pfam08477   2 VVLLGDSGVGKTSLLKRFVDDTFDPKYKSTIGVDFKTKTVLENDDngkkIKLNIWDTAGQ------ERfrslhpfYYRGA 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 530405957   92 HAFLVVYsvDSRQSFDSSSSYLELLAlHAKEtqrsIPALLLGNKLD 137
Cdd:pfam08477  76 AAALLVY--DSRTFSNLKYWLRELKK-YAGN----SPVILVGNKID 114

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530405957  20 EVNLAILGRRGAGKSALTVKFLTKRF-ISEYD-PNLEDTYSSEETVDHQPVHLRVMDTADLD----TPRNCERYLNWAHA 93
Cdd:COG1100    3 EKKIVVVGTGGVGKTSLVNRLVGDIFsLEKYLsTNGVTIDKKELKLDGLDVDLVIWDTPGQDefreTRQFYARQLTGASL 82

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530405957  94 FLVVYSVDSRQSFDSSSSYLELLALHAKEtqrsIPALLLGNKLD 137
Cdd:COG1100   83 YLFVVDGTREETLQSLYELLESLRRLGKK----SPIILVLNKID 122

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 530405957  25 ILGRRGAGKSALTVKFLTKRFiseyDPNLEDTYSSE-----ETVDHQPVHLRVMDTA------DLDTPrncerYLNWAHA 93
Cdd:cd04116   10 LLGDGGVGKSSLMNRYVTNKF----DTQLFHTIGVEflnkdLEVDGHFVTLQIWDTAgqerfrSLRTP-----FYRGSDC 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 530405957  94 FLVVYSVDSRQSFDSSSSYLELLALHAKETQ-RSIPALLLGNKLDMAQYRI 143
Cdd:cd04116   81 CLLTFSVDDSQSFQNLSNWKKEFIYYADVKEpESFPFVILGNKIDIPERQV 131

Rab GTPase family 14 (Rab14); Rab14 GTPases are localized to biosynthetic compartments, including the rough ER, the Golgi complex, and the trans-Golgi network, and to endosomal compartments, including early endosomal vacuoles and associated vesicles. Rab14 is believed to function in both the biosynthetic and recycling pathways between the Golgi and endosomal compartments. Rab14 has also been identified on GLUT4 vesicles, and has been suggested to help regulate GLUT4 translocation. In addition, Rab14 is believed to play a role in the regulation of 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 530405957  25 ILGRRGAGKSALTVKFLTKRFIseydPNLEDTYSSE-----ETVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVY 98
Cdd:cd04122    7 IIGDMGVGKSCLLHQFTEKKFM----ADCPHTIGVEfgtriIEVNGQKIKLQIWDTAGQERFRAVTRsYYRGAAGALMVY 82

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530405957  99 SVDSRQSFDSSSSYLEllalHAKE-TQRSIPALLLGNKLDMAQYR 142
Cdd:cd04122   83 DITRRSTYNHLSSWLT----DARNlTNPNTVIFLIGNKADLEAQR 123