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 82546836   1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153  37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 82546836  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153 117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

Arf-like 5 (Arl5) and 8 (Arl8) GTPases; Arl5/Arl8 subfamily. Arl5 (Arf-like 5) and Arl8, like Arl4 and Arl7, are localized to the nucleus and nucleolus. Arl5 is developmentally regulated during embryogenesis in mice. Human Arl5 interacts with the heterochromatin protein 1-alpha (HP1alpha), a nonhistone chromosomal protein that is associated with heterochromatin and telomeres, and prevents telomere fusion. Arl5 may also play a role in embryonic nuclear dynamics and/or signaling cascades. Arl8 was identified from a fetal cartilage cDNA library. It is found in brain, heart, lung, cartilage, and kidney. No function has been assigned for Arl8 to date.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153  37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 82546836  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153 117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

ARF-like small GTPases; ARF, ADP-ribosylation factor; Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836      1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:smart00177  35 LGESVTTIPTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDSNDRDRIDEAREELHRMLNEDELRD 114

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836     81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSRLK 140
Cdd:smart00177 115 AVILVFANKQDLPDAMKAAEITEKLGLHSIRDRNWYIQPTCATSGDGLYEGLTWLSNNLK 174

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   9 PTIGSNVEEIVI----NNTRFLMWDIGGQ---ESLRSSWNTYYTNTEFVIVVVDSTdrerISVTREELYKMLahEDLRKA 81
Cdd:COG1100  35 STNGVTIDKKELkldgLDVDLVIWDTPGQdefRETRQFYARQLTGASLYLFVVDGT----REETLQSLYELL--ESLRRL 108

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 82546836  82 G----LLIFANKQDvkeCMTVAEISQFLKLTSI--KDHQWHIQACCALTGEGL 128
Cdd:COG1100 109 GkkspIILVLNKID---LYDEEEIEDEERLKEAlsEDNIVEVVATSAKTGEGV 158

Arf-like 5 (Arl5) and 8 (Arl8) GTPases; Arl5/Arl8 subfamily. Arl5 (Arf-like 5) and Arl8, like Arl4 and Arl7, are localized to the nucleus and nucleolus. Arl5 is developmentally regulated during embryogenesis in mice. Human Arl5 interacts with the heterochromatin protein 1-alpha (HP1alpha), a nonhistone chromosomal protein that is associated with heterochromatin and telomeres, and prevents telomere fusion. Arl5 may also play a role in embryonic nuclear dynamics and/or signaling cascades. Arl8 was identified from a fetal cartilage cDNA library. It is found in brain, heart, lung, cartilage, and kidney. No function has been assigned for Arl8 to date.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04153  37 LGEVVHTSPTIGSNVEEIVYKNIRFLMWDIGGQESLRSSWNTYYTNTDAVILVIDSTDRERLPLTKEELYKMLAHEDLRK 116

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 82546836  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSR 138
Cdd:cd04153 117 AVLLVLANKQDLKGAMTPAEISESLGLTSIRDHTWHIQGCCALTGEGLPEGLDWIASR 174

ADP-ribosylation factor family; Pfam combines a number of different Prosite families together

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836     1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:pfam00025  22 LGEIVTTIPTIGFNVETVTYKNVKFTVWDVGGQESLRPLWRNYFPNTDAVIFVVDSADRDRIEEAKEELHALLNEEELAD 101

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 82546836    81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:pfam00025 102 APLLILANKQDLPGAMSEAEIRELLGLHELKDRPWEIQGCSAVTGEGLDEGLDWL 156

ARF-like small GTPases; ARF, ADP-ribosylation factor; Ras homologues involved in vesicular transport. Activator of phospholipase D isoforms. Unlike Ras proteins they lack cysteine residues at their C-termini and therefore are unlikely to be prenylated. ARFs are N-terminally myristoylated. Contains ATP/GTP-binding motif (P-loop).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836      1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:smart00177  35 LGESVTTIPTIGFNVETVTYKNISFTVWDVGGQDKIRPLWRHYYTNTQGLIFVVDSNDRDRIDEAREELHRMLNEDELRD 114

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836     81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWMMSRLK 140
Cdd:smart00177 115 AVILVFANKQDLPDAMKAAEITEKLGLHSIRDRNWYIQPTCATSGDGLYEGLTWLSNNLK 174

ADP-ribosylation factor-1 (Arf1) and ADP-ribosylation factor-5 (Arf5); The Arf1-Arf5-like subfamily contains Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Arfs1-5 are soluble proteins that are crucial for assembling coat proteins during vesicle formation. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor. Arf4 has also been shown to recognize the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialized post-Golgi rhodopsin transport carriers (RTCs). There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   3 EVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAG 82
Cdd:cd04150  24 EIVTTIPTIGFNVETVEYKNISFTVWDVGGQDKIRPLWRHYFQNTQGLIFVVDSNDRERIGEAREELQRMLNEDELRDAV 103

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 82546836  83 LLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04150 104 LLVFANKQDLPNAMSAAEVTDKLGLHSLRNRNWYIQATCATSGDGLYEGLDWL 156

Arf-like 3 (Arl3) GTPase; Arl3 (Arf-like 3) is an Arf family protein that differs from most Arf family members in the N-terminal extension. In is inactive, GDP-bound form, the N-terminal extension forms an elongated loop that is hydrophobically anchored into the membrane surface; however, it has been proposed that this region might form a helix in the GTP-bound form. The delta subunit of the rod-specific cyclic GMP phosphodiesterase type 6 (PDEdelta) is an Arl3 effector. Arl3 binds microtubules in a regulated manner to alter specific aspects of cytokinesis via interactions with retinitis pigmentosa 2 (RP2). It has been proposed that RP2 functions in concert with Arl3 to link the cell membrane and the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery. In mice, the absence of Arl3 is associated with abnormal epithelial cell proliferation and cyst formation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   3 EVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAG 82
Cdd:cd04155  39 DISHITPTQGFNIKNVQADGFKLNVWDIGGQRKIRPYWRNYFENTDVLIYVIDSADRKRFEEAGQELVELLEEEKLAGVP 118

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 82546836  83 LLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEW 134
Cdd:cd04155 119 VLVFANKQDLLTAAPAEEVAEALNLHDIRDRSWHIQACSAKTGEGLQEGMNW 170

ADP ribosylation factor 6 (Arf6); Arf6 subfamily. Arf6 (ADP ribosylation factor 6) proteins localize to the plasma membrane, where they perform a wide variety of functions. In its active, GTP-bound form, Arf6 is involved in cell spreading, Rac-induced formation of plasma membrane ruffles, cell migration, wound healing, and Fc-mediated phagocytosis. Arf6 appears to change the actin structure at the plasma membrane by activating Rac, a Rho family protein involved in membrane ruffling. Arf6 is required for and enhances Rac formation of ruffles. Arf6 can regulate dendritic branching in hippocampal neurons, and in yeast it localizes to the growing bud, where it plays a role in polarized growth and bud site selection. In leukocytes, Arf6 is required for chemokine-stimulated migration across endothelial cells. Arf6 also plays a role in down-regulation of beta2-adrenergic receptors and luteinizing hormone receptors by facilitating the release of sequestered arrestin to allow endocytosis. Arf6 is believed to function at multiple sites on the plasma membrane through interaction with a specific set of GEFs, GAPs, and effectors. Arf6 has been implicated in breast cancer and melanoma cell invasion, and in actin remodelling at the invasion site of Chlamydia infection.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   1 MNEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRK 80
Cdd:cd04149  31 LGQSVTTIPTVGFNVETVTYKNVKFNVWDVGGQDKIRPLWRHYYTGTQGLIFVVDSADRDRIDEARQELHRIINDREMRD 110

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 82546836  81 AGLLIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04149 111 ALLLVFANKQDLPDAMKPHEIQEKLGLTRIRDRNWYVQPSCATSGDGLYEGLTWL 165

Arf-like 6 (Arl6) GTPase; Arl6 (Arf-like 6) forms a subfamily of the Arf family of small GTPases. Arl6 expression is limited to the brain and kidney in adult mice, but it is expressed in the neural plate and somites during embryogenesis, suggesting a possible role for Arl6 in early development. Arl6 is also believed to have a role in cilia or flagella function. Several proteins have been identified that bind Arl6, including Arl6 interacting protein (Arl6ip), and SEC61beta, a subunit of the heterotrimeric conducting channel SEC61p. Based on Arl6 binding to these effectors, Arl6 is also proposed to play a role in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. At least three specific homozygous Arl6 mutations in humans have been found to cause Bardet-Biedl syndrome, a disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   6 HTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDL--RKAGL 83
Cdd:cd04157  28 NIVPTVGFNVESFKKGNLSFTAFDMSGQGKYRGLWEHYYKNIQGIIFVIDSSDRLRMVVAKDELELLLNHPDIkhRRIPI 107

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 82546836  84 LIFANKQDVKECMTVAEISQFLKLTSIKDHQWHIQACCALTGEGLCQGLEWM 135
Cdd:cd04157 108 LFYANKMDLPDALTAVKITQLLCLENIKDKPWHIFASSALTGEGLDEGVDWL 159

(ADP-ribosylation factor domain protein 1 (ARD1); ARD1 (ADP-ribosylation factor domain protein 1) is an unusual member of the Arf family. In addition to the C-terminal Arf domain, ARD1 has an additional 46-kDa N-terminal domain that contains a RING finger domain, two predicted B-Boxes, and a coiled-coil protein interaction motif. This domain belongs to the TRIM (tripartite motif) or RBCC (RING, B-Box, coiled-coil) family. Like most Arfs, the ARD1 Arf domain lacks detectable GTPase activity. However, unlike most Arfs, the full-length ARD1 protein has significant GTPase activity due to the GAP (GTPase-activating protein) activity exhibited by the 46-kDa N-terminal domain. The GAP domain of ARD1 is specific for its own Arf domain and does not bind other Arfs. The rate of GDP dissociation from the ARD1 Arf domain is slowed by the adjacent 15 amino acids, which act as a GDI (GDP-dissociation inhibitor) domain. ARD1 is ubiquitously expressed in cells and localizes to the Golgi and to the lysosomal membrane. Two Tyr-based motifs in the Arf domain are responsible for Golgi localization, while the GAP domain controls lysosomal localization.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   2 NEVVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKA 81
Cdd:cd04158  22 DEFMQPIPTIGFNVETVEYKNLKFTIWDVGGKHKLRPLWKHYYLNTQAVVFVIDSSHRDRVSEAHSELAKLLTEKELRDA 101

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 82546836  82 GLLIFANKQDVKECMTVAEISQFLKLTSI-KDHQWHIQACCALTGEGLCQGLEWMMSRL 139
Cdd:cd04158 102 LLLIFANKQDVAGALSVEEMTELLSLHKLcCGRSWYIQGCDARSGMGLYEGLDWLSRQL 160

Arf-like 9 (Arl9) and 10 (Arl10) GTPases; Arl10-like subfamily. Arl9/Arl10 was identified from a human cancer-derived EST dataset. No functional information about the subfamily is available at the current time, but crystal structures of human Arl10b and Arl10c have been solved.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   4 VVHTSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGL 83
Cdd:cd04159  25 SEDTIPTVGFNMRKVTKGNVTIKVWDLGGQPRFRSMWERYCRGVNAIVYVVDAADREKLEVAKNELHDLLEKPSLEGIPL 104

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 82546836  84 LIFANKQDVKECMTVAEISQFLKLTSIKDHQWhiqaCC----ALTGEGLCQGLEWMMSR 138
Cdd:cd04159 105 LVLGNKNDLPGALSVDELIEQMNLKSITDREV----SCysisAKEKTNIDIVLDWLIKH 159

Arf-like 9 (Arl9)/Arfrp2-like GTPase; Arl9/Arfrp2-like subfamily. Arl9 (Arf-like 9) was first identified as part of the Human Cancer Genome Project. It maps to chromosome 4q12 and is sometimes referred to as Arfrp2 (Arf-related protein 2). This is a novel subfamily identified in human cancers that is uncharacterized to date.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   7 TSPTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHE-DLRkagLLI 85
Cdd:cd04162  28 VVPTTGFNSVAIPTQDAIMELLEIGGSQNLRKYWKRYLSGSQGLIFVVDSADSERLPLARQELHQLLQHPpDLP---LVV 104

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 82546836  86 FANKQDVKECMTVAEISQFLKLTSI-KDHQWHIQAC 120
Cdd:cd04162 105 LANKQDLPAARSVQEIHKELELEPIaRGRRWILQGT 140

Sar1p-like members of the Ras-family of small GTPases; Yeast SAR1 is an essential gene required for transport of secretory proteins from the endoplasmic reticulum to the Golgi apparatus.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836      9 PTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLIFAN 88
Cdd:smart00178  47 PTQHPTSEELAIGNIKFTTFDLGGHQQARRLWKDYFPEVNGIVYLVDAYDKERFAESKRELDALLSDEELATVPFLILGN 126

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 82546836     89 KQDVKECMTVAEISQFLKLTSIKDHQWHIQA-------CCALTGEGLCQGLEWM 135
Cdd:smart00178 127 KIDAPYAASEDELRYALGLTNTTTGKGKVGVrpvevfmCSVVRRMGYGEGFKWL 180

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 82546836   6 HTSPTIGSN--VEEIVINNTRFLM--WDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRErisvTREELYKMLahEDLRKA 81
Cdd:cd00154  28 NYKSTIGVDfkSKTIEVDGKKVKLqiWDTAGQERFRSITSSYYRGAHGAILVYDVTNRE----SFENLDKWL--NELKEY 101

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 82546836  82 G-----LLIFANKQDVKECMTV--AEISQFlkltsIKDHQWHIQACCALTGEG 127
Cdd:cd00154 102 AppnipIILVGNKSDLEDERQVstEEAQQF-----AKENGLLFFETSAKTGEN 149

Rab GTPase family 35 (Rab35); Rab35 is one of several Rab proteins to be found to participate in the regulation of osteoclast cells in rats. In addition, Rab35 has been identified as a protein that interacts with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in human cells. Overexpression of NPM-ALK is a key oncogenic event in some anaplastic large-cell lymphomas; since Rab35 interacts with N|PM-ALK, it may provide a target for cancer treatments. 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 82546836  10 TIGSN--VEEIVINNTR--FLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLi 85
Cdd:cd04110  38 TIGVDfkIRTVEINGERvkLQIWDTAGQERFRTITSTYYRGTHGVIVVYDVTNGESFVNVKRWLQEIEQNCDDVCKVLV- 116

                ....*.
gi 82546836  86 fANKQD 91
Cdd:cd04110 117 -GNKND 121

Signal recognition particle receptor, beta subunit (SR-beta), together with SR-alpha, forms the heterodimeric signal recognition particle (SRP); Signal recognition particle receptor, beta subunit (SR-beta). SR-beta and SR-alpha form the heterodimeric signal recognition particle (SRP or SR) receptor that binds SRP to regulate protein translocation across the ER membrane. Nascent polypeptide chains are synthesized with an N-terminal hydrophobic signal sequence that binds SRP54, a component of the SRP. SRP directs targeting of the ribosome-nascent chain complex (RNC) to the ER membrane via interaction with the SR, which is localized to the ER membrane. The RNC is then transferred to the protein-conducting channel, or translocon, which facilitates polypeptide translation across the ER membrane or integration into the ER membrane. SR-beta is found only in eukaryotes; it is believed to control the release of the signal sequence from SRP54 upon binding of the ribosome to the translocon. High expression of SR-beta has been observed in human colon cancer, suggesting it may play a role in the development of this type of cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   6 HTS--PTIGSNVEEIViNNTRFLMWDIGGQESLRSSWNTYYTNTEFVIV-VVDSTDRER-ISVTREELYKMLAHEDLRKA 81
Cdd:cd04105  29 VTSiePNVASFYSNSS-KGKKLTLVDVPGHEKLRDKLLEYLKASLKAIVfVVDSATFQKnIRDVAEFLYDILTDLEKIKN 107

                        90
                ....*....|...
gi 82546836  82 G--LLIFANKQDV 92
Cdd:cd04105 108 KipILIACNKQDL 120

G-protein alpha subunit; G proteins couple receptors of extracellular signals to intracellular signaling pathways. The G protein alpha subunit binds guanyl nucleotide and is a weak GTPase. A set of residues that are unique to G-alpha as compared to its ancestor the Arf-like family form a ring of residues centered on the nucleotide binding site. A Ggamma is found fused to an inactive Galpha in the Dictyostelium protein gbqA.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836     4 VVHTS-PTIGSNVEEIVINNTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVV-----DSTDRERISVTR-EE---LYK-M 72
Cdd:pfam00503 147 ILRARvKTTGIIETKFEFKGLKFRLFDVGGQRSERKKWIHCFEDVTAIIFVVslseyDQVLYEDDSTNRmEEslkLFEeI 226

                          90       100
                  ....*....|....*....|
gi 82546836    73 LAHEDLRKAGLLIFANKQDV 92
Cdd:pfam00503 227 CNSPWFKNTPIILFLNKKDL 246

Rab GTPase families 34 (Rab34) and 36 (Rab36); Rab34/Rab36 subfamily. Rab34, found primarily in the Golgi, interacts with its effector, Rab-interacting lysosomal protein (RILP). This enables its participation in microtubular dynenin-dynactin-mediated repositioning of lysosomes from the cell periphery to the Golgi. A Rab34 (Rah) isoform that lacks the consensus GTP-binding region has been identified in mice. This isoform is associated with membrane ruffles and promotes macropinosome formation. Rab36 has been mapped to human chromosome 22q11.2, a region that is homozygously deleted in malignant rhabdoid tumors (MRTs). However, experimental assessments do not implicate Rab36 as a tumor suppressor that would enable tumor formation through a loss-of-function mechanism. 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 82546836  27 MWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKMLAHEDLRKAGLLIFANKQDVKECMTVAEISQ-FL 105
Cdd:cd04108  53 LWDTAGQERFKCIASTYYRGAQAIIIVFDLTDVASLEHTRQWLEDALKENDPSSVLLFLVGTKKDLSSPAQYALMEQdAI 132

                        90       100
                ....*....|....*....|....
gi 82546836 106 KLT-SIKDHQWhiqACCALTGEGL 128
Cdd:cd04108 133 KLArEMKAEYW---AVSALTGENV 153

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 82546836     6 HTSPTIGSNV--EEIVINNT-----RFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERIsvtrEELYKMLaHEDL 78
Cdd:pfam08477  27 KYKSTIGVDFktKTVLENDDngkkiKLNIWDTAGQERFRSLHPFYYRGAAAALLVYDSRTFSNL----KYWLREL-KKYA 101

                          90
                  ....*....|...
gi 82546836    79 RKAGLLIFANKQD 91
Cdd:pfam08477 102 GNSPVILVGNKID 114

Rab GTPase family 4 (Rab4); Rab4 subfamily. Rab4 has been implicated in numerous functions within the cell. It helps regulate endocytosis through the sorting, recycling, and degradation of early endosomes. Mammalian Rab4 is involved in the regulation of many surface proteins including G-protein-coupled receptors, transferrin receptor, integrins, and surfactant protein A. Experimental data implicate Rab4 in regulation of the recycling of internalized receptors back to the plasma membrane. It is also believed to influence receptor-mediated antigen processing in B-lymphocytes, in calcium-dependent exocytosis in platelets, in alpha-amylase secretion in pancreatic cells, and in insulin-induced translocation of Glut4 from internal vesicles to the cell surface. Rab4 is known to share effector proteins with Rab5 and Rab11. 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 82546836   7 TSPTIGSNVEEIVIN----NTRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREEL--YKMLAHEDLRk 80
Cdd:cd04113  29 SNHTIGVEFGSRVVNvggkSVKLQIWDTAGQERFRSVTRSYYRGAAGALLVYDITSRESFNALTNWLtdARTLASPDIV- 107

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 82546836  81 agLLIFANKQDVKEC--MTVAEISQFlkltsIKDHQWHIQACCALTGEGL 128
Cdd:cd04113 108 --IILVGNKKDLEDDreVTFLEASRF-----AQENGLLFLETSALTGENV 150

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   18 IVINN--TRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDstdrerisVTREELYKMLAH--EDLRKAG-----LLIFAN 88
Cdd:PLN03108  48 ITIDNkpIKLQIWDTAGQESFRSITRSYYRGAAGALLVYD--------ITRRETFNHLASwlEDARQHAnanmtIMLIGN 119

                         90       100
                 ....*....|....*....|
gi 82546836   89 KQDV--KECMTVAEISQFLK 106
Cdd:PLN03108 120 KCDLahRRAVSTEEGEQFAK 139

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 82546836     9 PTIG--SNVEEIVINNTRFLM--WDIGGQE---SLRSSwntYYTNTEFVIVVVDSTDR---ERISVTREELykmlahedL 78
Cdd:pfam00071  30 PTIGvdFYTKTIEVDGKTVKLqiWDTAGQErfrALRPL---YYRGADGFLLVYDITSRdsfENVKKWVEEI--------L 98

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 82546836    79 RKAG----LLIFANKQDVKE--CMTVAEISQFLKltsikdhQWHIQ--ACCALTGEG 127
Cdd:pfam00071  99 RHADenvpIVLVGNKCDLEDqrVVSTEEGEALAK-------ELGLPfmETSAKTNEN 148

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 82546836   6 HTSPTIGS-------NVEEIVInntRFLMWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTReELYKMLAHEDL 78
Cdd:cd01861  28 QYQATIGIdflsktmYVDDKTV---RLQLWDTAGQERFRSLIPSYIRDSSVAVVVYDITNRQSFDNTD-KWIDDVRDERG 103

                        90       100
                ....*....|....*....|
gi 82546836  79 RKAGLLIFANKQDVKECMTV 98
Cdd:cd01861 104 NDVIIVLVGNKTDLSDKRQV 123

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 82546836  27 MWDIGGQESLRSSWNTYYTNTEFVIVVVDSTDRERISVTREELYKM--LAHEDLRKaglLIFANKQDV--KECMTVAEIS 102
Cdd:cd01869  55 IWDTAGQERFRTITSSYYRGAHGIIIVYDVTDQESFNNVKQWLQEIdrYASENVNK---LLVGNKCDLtdKKVVDYTEAK 131

                ....*...
gi 82546836 103 QFLKLTSI 110
Cdd:cd01869 132 EFADELGI 139

Ras-related nuclear proteins (Ran)/TC4 family of small GTPases; Ran GTPase is involved in diverse biological functions, such as nuclear transport, spindle formation during mitosis, DNA replication, and cell division. Among the Ras superfamily, Ran is a unique small G protein. It does not have a lipid modification motif at the C-terminus to bind to the membrane, which is often observed within the Ras superfamily. Ran may therefore interact with a wide range of proteins in various intracellular locations. Like other GTPases, Ran exists in GTP- and GDP-bound conformations that interact differently with effectors. Conversion between these forms and the assembly or disassembly of effector complexes requires the interaction of regulator proteins. The intrinsic GTPase activity of Ran is very low, but it is greatly stimulated by a GTPase-activating protein (RanGAP1) located in the cytoplasm. By contrast, RCC1, a guanine nucleotide exchange factor that generates RanGTP, is bound to chromatin and confined to the nucleus. Ran itself is mobile and is actively imported into the nucleus by a mechanism involving NTF-2. Together with the compartmentalization of its regulators, this is thought to produce a relatively high concentration of RanGTP in the nucleus.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82546836   9 PTIGSNVEEIVINNT----RFLMWDIGGQE---SLRSSwntYYTNTEFVIVVVDSTDRerisVTreelYKMLA--HEDL- 78
Cdd:cd00877  31 ATLGVEVHPLDFHTNrgkiRFNVWDTAGQEkfgGLRDG---YYIQGQCAIIMFDVTSR----VT----YKNVPnwHRDLv 99

                        90       100       110
                ....*....|....*....|....*....|.
gi 82546836  79 RKAG---LLIFANKQDVKECMTVAEISQFLK 106
Cdd:cd00877 100 RVCEnipIVLCGNKVDIKDRKVKPKQITFHR 130