4JHN , 4JHP , 4QAM
32-507: 6103 19893 ENSG00000156313 ENSMUSG00000031174 Q92834 Q9R0X5 NM_000328 NM_001023582 NM_001034853 NM_011285 NP_001354177 NP_001354178 NP_001354179 NP_001354180 NP_035415 X-linked retinitis pigmentosa GTPase regulator is a GTPase -binding protein that in humans is encoded by the RPGR gene . The gene is located on the X-chromosome and
64-863: A P-loop from a superclass other than the G-domain-containing one. Examples include the NACHT proteins of its own superclass and McrB protein of the AAA+ superclass. Hydrolase In biochemistry , hydrolases constitute a class of enzymes that commonly function as biochemical catalysts that use water to break a chemical bond : This typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are esterases including lipases , phosphatases , glycosidases , peptidases , and nucleosidases . Esterases cleave ester bonds in lipids and phosphatases cleave phosphate groups off molecules. An example of crucial esterase
96-538: A ciliary protein that is mutated in Usher Syndrome. The RPGR isoform has been shown to be glutamylated on its N-terminus by tubulin-tyrosine ligase-like 5 (TTLL5). It has also been shown that loss of TTLL5 mimics loss of RPGR in the mouse retina. GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP) . The GTP binding and hydrolysis takes place in
128-400: A discussion of Translocation factors and the role of GTP, see signal recognition particle (SRP). While tubulin and related structural proteins also bind and hydrolyze GTP as part of their function to form intracellular tubules, these proteins utilize a distinct tubulin domain that is unrelated to the G domain used by signaling GTPases. There are also GTP-hydrolyzing proteins that use
160-457: Is acetylcholine esterase , which assists in transforming the neuron impulse into the acetate group after the hydrolase breaks the acetylcholine into choline and acetic acid . Acetic acid is an important metabolite in the body and a critical intermediate for other reactions such as glycolysis . Lipases hydrolyze glycerides . Glycosidases cleave sugar molecules off carbohydrates and peptidases hydrolyze peptide bonds . Nucleosidases hydrolyze
192-401: Is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments. This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of
224-619: Is defined by loss of two beta-strands and additional N-terminal strands. Both namesakes of this superfamily, myosin and kinesin , have shifted to use ATP. See dynamin as a prototype for large monomeric GTPases. Much of the SIMIBI class of GTPases is activated by dimerization. Named after the signal recognition particle (SRP), MinD, and BioD, the class is involved in protein localization, chromosome partitioning, and membrane transport. Several members of this class, including MinD and Get3, has shifted in substrate specificity to become ATPases. For
256-468: Is named after the prototypical member, the translation factor G proteins. They play roles in translation, signal transduction, and cell motility. Multiple classical translation factor family GTPases play important roles in initiation , elongation and termination of protein biosynthesis . Sharing a similar mode of ribosome binding due to the β-EI domain following the GTPase, the most well-known members of
288-572: Is returned to being GDP bound, the two parts of the heterotrimer re-associate to the original, inactive state. The heterotrimeric G proteins can be classified by sequence homology of the α unit and by their functional targets into four families: G s family, G i family, G q family and G 12 family. Each of these G α protein families contains multiple members, such that the mammals have 16 distinct α -subunit genes. The G β and G γ are likewise composed of many members, increasing heterotrimer structural and functional diversity. Among
320-461: Is terminated by hydrolysis of bound GTP to bound GDP. This can occur through the intrinsic GTPase activity of the α subunit, or be accelerated by separate regulatory proteins that act as GTPase-activating proteins (GAPs), such as members of the Regulator of G protein signaling (RGS) family). The speed of the hydrolysis reaction works as an internal clock limiting the length of the signal. Once G α
352-418: The phototransduction cascade takes place. RPGR is primarily located in a protein complex in the connecting cilium and is involved in regulating the cargo that is trafficked from the inner segment to the outer segment. Retinitis pigmentosa GTPase regulator has been shown to interact with PDE6D nephronophthisis (NPHP) proteins and RPGRIP1 . Binding to PDE6D has been shown to ensure ciliary localization of
SECTION 10
#1732855523000384-550: The G protein complex and to promote binding of GTP in its place. The GTP-bound complex undergoes an activating conformation shift that dissociates it from the receptor and also breaks the complex into its component G protein alpha and beta-gamma subunit components. While these activated G protein subunits are now free to activate their effectors, the active receptor is likewise free to activate additional G proteins – this allows catalytic activation and amplification where one receptor may activate many G proteins. G protein signaling
416-486: The GTP binding/GTPase domain flanked by long regulatory regions, while the beta and gamma subunits form a stable dimeric complex referred to as the beta-gamma complex . When activated, a heterotrimeric G protein dissociates into activated, GTP-bound alpha subunit and separate beta-gamma subunit, each of which can perform distinct signaling roles. The α and γ subunit are modified by lipid anchors to increase their association with
448-511: The RPGR isoform contains a CTIL motif (812CTIL815) which recruits prenyl-binding protein PDE6D which then shuttles the protein to the connecting cilium. Photoreceptor cells contain an inner segment and an outer segment which are joined by a connecting cilium . Protein synthesis occurs exclusively in the inner segment and all proteins must be trafficked across the connecting cilium to the outer segment where
480-610: The RPGR isoform. Additionally, the N-terminal of interacts with a PDE6D interacting protein, INPP5E (inositol polyphosphatase 5E). INPP5E has been shown to regulates phosphoinositide metabolism and may modulate the phosphoinositide content of photoreceptor cells. RPGR has also been shown to preferentially interact with the GDP-bound form of the small GTPase RAB8A. RAB8A is involved in rhodopsin trafficking in primary cilia. The C-terminal domain of RPGR has been shown to interact with whirlin,
512-483: The active lifetime of signaling GTPases. Some GTPases have little to no intrinsic GTPase activity, and are entirely dependent on GAP proteins for deactivation (such as the ADP-ribosylation factor or ARF family of small GTP-binding proteins that are involved in vesicle-mediated transport within cells). To become activated, GTPases must bind to GTP. Since mechanisms to convert bound GDP directly into GTP are unknown,
544-411: The active, GTP-bound protein to the inactive, GDP-bound state. Most "GTPases" have functional GTPase activity, allowing them to remain active (that is, bound to GTP) only for a short time before deactivating themselves by converting bound GTP to bound GDP. However, many GTPases also use accessory proteins named GTPase-activating proteins or GAPs to accelerate their GTPase activity. This further limits
576-428: The activity of effector proteins. This inactive-active switch is due to conformational changes in the protein distinguishing these two forms, particularly of the "switch" regions that in the active state are able to make protein-protein contacts with partner proteins that alter the function of these effectors. Hydrolysis of GTP bound to an (active) G domain-GTPase leads to deactivation of the signaling/timer function of
608-472: The bonds of nucleotides . Hydrolase enzymes are important for the body because they have degradative properties. In lipids, lipases contribute to the breakdown of fats and lipoproteins and other larger molecules into smaller molecules like fatty acids and glycerol . Fatty acids and other small molecules are used for synthesis and as a source of energy. Systematic names of hydrolases are formed as " substrate hydrolase." However, common names are typically in
640-403: The digestion of food. Many hydrolases, and especially proteases associate with biological membranes as peripheral membrane proteins or anchored through a single transmembrane helix . Some others are multi-span transmembrane proteins , for example rhomboid protease . The word hydrolase ( / ˈ h aɪ d r oʊ l eɪ s , - l eɪ z / ) suffixes the combining form of -ase to
672-405: The enzyme. The hydrolysis of the third (γ) phosphate of GTP to create guanosine diphosphate (GDP) and P i , inorganic phosphate , occurs by the S N 2 mechanism (see nucleophilic substitution ) via a pentacoordinate transition state and is dependent on the presence of a magnesium ion Mg . GTPase activity serves as the shutoff mechanism for the signaling roles of GTPases by returning
SECTION 20
#1732855523000704-608: The family are EF-1A / EF-Tu , EF-2 / EF-G , and class 2 release factors . Other members include EF-4 (LepA), BipA (TypA), SelB (bacterial selenocysteinyl-tRNA EF-Tu paralog), Tet ( tetracycline resistance by ribosomal protection), and HBS1L (eukaryotic ribosome rescue protein similar to release factors). The superfamily also includes the Bms1 family from yeast. Heterotrimeric G protein complexes are composed of three distinct protein subunits named alpha (α), beta (β) and gamma (γ) subunits . The alpha subunits contain
736-838: The first-identified such protein, named Ras , they are also referred to as Ras superfamily GTPases. Small GTPases generally serve as molecular switches and signal transducers for a wide variety of cellular signaling events, often involving membranes, vesicles or cytoskeleton. According to their primary amino acid sequences and biochemical properties, the many Ras superfamily small GTPases are further divided into five subfamilies with distinct functions: Ras , Rho ("Ras-homology"), Rab , Arf and Ran . While many small GTPases are activated by their GEFs in response to intracellular signals emanating from cell surface receptors (particularly growth factor receptors ), regulatory GEFs for many other small GTPases are activated in response to intrinsic cell signals, not cell surface (external) signals. This class
768-455: The form " substrate base ". For example, a nuclease is a hydrolase that cleaves nucleic acids . Hydrolases are classified as EC 3 in the EC number classification of enzymes. Hydrolases can be further classified into several subclasses, based upon the bonds they act upon: Hydrolase secreted by Lactobacillus jensenii in the human gut stimulates the liver to secrete bile salts that aids in
800-472: The highly conserved P-loop "G domain", a protein domain common to many GTPases. GTPases function as molecular switches or timers in many fundamental cellular processes. Examples of these roles include: GTPases are active when bound to GTP and inactive when bound to GDP. In the generalized receptor-transducer-effector signaling model of Martin Rodbell , signaling GTPases act as transducers to regulate
832-450: The highly conserved guanine nucleotide exchange factors. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. The two major isoforms are RPGR, the default isoform, composed of exons 1-19, and RPGR which retains part of intron 15 as
864-399: The inactive GTPases are induced to release bound GDP by the action of distinct regulatory proteins called guanine nucleotide exchange factors or GEFs. The nucleotide-free GTPase protein quickly rebinds GTP, which is in far excess in healthy cells over GDP, allowing the GTPase to enter the active conformation state and promote its effects on the cell. For many GTPases, activation of GEFs is
896-483: The inactive, GDP-bound state. The amount of active GTPase can be changed in several ways: In most GTPases, the specificity for the base guanine versus other nucleotides is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. The following classification is based on shared features; some examples have mutations in the base-recognition motif that shift their substrate specificity, most commonly to ATP. The TRAFAC class of G domain proteins
928-495: The inner leaflet of the plasma membrane. Heterotrimeric G proteins act as the transducers of G protein-coupled receptors , coupling receptor activation to downstream signaling effectors and second messengers . In unstimulated cells, heterotrimeric G proteins are assembled as the GDP bound, inactive trimer (G α -GDP-G βγ complex). Upon receptor activation, the activated receptor intracellular domain acts as GEF to release GDP from
960-592: The primary control mechanism in the stimulation of the GTPase signaling functions, although GAPs also play an important role. For heterotrimeric G proteins and many small GTP-binding proteins, GEF activity is stimulated by cell surface receptors in response to signals outside the cell (for heterotrimeric G proteins, the G protein-coupled receptors are themselves GEFs, while for receptor-activated small GTPases their GEFs are distinct from cell surface receptors). Some GTPases also bind to accessory proteins called guanine nucleotide dissociation inhibitors or GDIs that stabilize
992-518: The target molecules of the specific G proteins are the second messenger-generating enzymes adenylyl cyclase and phospholipase C , as well as various ion channels . Small GTPases function as monomers and have a molecular weight of about 21 kilodaltons that consists primarily of the GTPase domain. They are also called small or monomeric guanine nucleotide-binding regulatory proteins, small or monomeric GTP-binding proteins, or small or monomeric G-proteins, and because they have significant homology with
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1024-444: The terminal exon . ORF15 is the terminal exon of RPGR and is a mutational hotspot accounting for ~60% of RPGR patients with heterogeneous diseases ranging from XLRP to cone-rod degeneration and macular degeneration. Alternatively, the RPGR isoform contains a putative prenylation domain on its C-terminal end which is involved in posttranslational modification and allows membrane-association and protein trafficking. The C-terminal domain of
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