Guanosine nucleotide dissociation inhibitor

Last updated
GDP dissociation inhibitor
PDB 2bcg EBI.jpg
structure of doubly prenylated ypt1:gdi complex
Identifiers
SymbolGDI
Pfam PF00996
Pfam clan CL0063
InterPro IPR018203
SCOPe 1gnd / SUPFAM

In molecular biology, the Guanosine dissociation inhibitors (GDIs) constitute a family of small GTPases that serve a regulatory role in vesicular membrane traffic. GDIs bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange (maintaining the small GTPase in an off-state), but also prevent the small GTPase from localizing at the membrane, which is their place of action. This inhibition can be removed by the action of a GDI displacement factor. [1] GDIs also inhibit cdc42 by binding to its tail and preventing its insertion into membranes; hence it cannot trigger WASPs and cannot lead to nucleation of F-actin.

The GDIs' C-terminal geranylgeranylation is crucial for their membrane association and function. [2] [3] This post-translational modification is catalysed by Rab geranylgeranyl transferase (Rab-GGTase), a multi-subunit enzyme that contains a catalytic heterodimer and an accessory component, termed Rab escort protein (REP)-1. [2] REP-1 presents newly synthesised Rab proteins to the catalytic component, and forms a stable complex with the prenylated proteins following the transfer reaction. The mechanism of REP-1-mediated membrane association of Rab5 is similar to that mediated by Rab GDP dissociation inhibitor (GDI). REP-1 and Rab GDI also share other functional properties, including the ability to inhibit the release of GDP and to remove Rab proteins from membranes.

The crystal structure of the bovine alpha-isoform of Rab GDI has been determined to a resolution of 1.81 Angstrom. [4] The protein is composed of two main structural units: a large complex multi-sheet domain I, and a smaller alpha-helical domain II.

The structural organisation of domain I is closely related to FAD-containing monooxygenases and oxidases. [4] Conserved regions common to GDI and the choroideraemia gene product, which delivers Rab to catalytic subunits of Rab geranylgeranyltransferase II, are clustered on one face of the domain. [3] The two most conserved regions form a compact structure at the apex of the molecule; site-directed mutagenesis has shown these regions to play a critical role in the binding of Rab proteins. [4]

Related Research Articles

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 the highly conserved G domain common to many GTPases.

Ras GTPase GTP-binding proteins functioning on cell-cycle regulation

Ras is a family of related proteins which is expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

The Rab family of proteins is a member of the Ras superfamily of small G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helixes. Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.

Prenylation Term from the Systems Biology Ontology

Prenylation is the addition of hydrophobic molecules to a protein or chemical compound. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups have been shown to be important for protein–protein binding through specialized prenyl-binding domains.

Rab geranylgeranyltransferase class of enzyme complexes

Rab geranylgeranyltransferase also known as (protein) geranylgeranyltransferase II is one of the three prenyltransferases. It transfers (usually) two geranylgeranyl groups to the cystein(s) at the C-terminus of Rab proteins.

Guanine nucleotide exchange factor Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

GTP-binding protein regulators

GTP-binding protein regulators regulate G proteins in several different ways. Small GTPases act as molecular switches in signaling pathways, which act to regulate functions of other proteins. They are active or 'ON' when it is bound to GTP and inactive or 'OFF' when bound to GDP. Activation and deactivation of small GTPases can be regarded as occurring in a cycle, between the GTP-bound and GDP-bound form, regulated by other regulatory proteins.

Rab escort protein 1 protein-coding gene in the species Homo sapiens

Rab escort protein 1 (REP1) also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.

RAB5A protein-coding gene in the species Homo sapiens

Ras-related protein Rab-5A is a protein that in humans is encoded by the RAB5A gene.

GDI1 protein-coding gene in the species Homo sapiens

Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the GDI1 gene.

G alpha subunit InterPro Family

G alpha subunits are one of the three types of subunit of guanine nucleotide binding proteins, which are membrane-associated, heterotrimeric G proteins.

ARHGDIA protein-coding gene in the species Homo sapiens

Rho GDP-dissociation inhibitor 1 is a protein that in humans is encoded by the ARHGDIA gene.

ARHGDIB protein-coding gene in the species Homo sapiens

Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.

GDI2 protein-coding gene in the species Homo sapiens

Rab GDP dissociation inhibitor beta is a protein that in humans is encoded by the GDI2 gene.

RABAC1 protein-coding gene in the species Homo sapiens

RABAC1 is a gene that in humans encodes the protein Prenylated Rab acceptor 1, also called PRA1, PRAF1, or RABAC1. It is highly conserved in eukaryotes. The protein is localized to Golgi and late endosomes, where it plays a role in vesicular trafficking, lipid transport and cell migration.

ARHGDIG protein-coding gene in the species Homo sapiens

Rho GDP-dissociation inhibitor 3 is a protein that in humans is encoded by the ARHGDIG gene.

GoLoco motif InterPro Conserved Site

GoLoco motif is a protein structural motif.

The TBC (Tre-2/Bub2/Cdc16) is identified as a domain of some proteins or as a protein motif and widely recognized as a conserved one that includes approximately 200 amino acids in all eukaryotes.

RAB2B protein-coding gene in the species Homo sapiens

Ras-related protein Rab-2B is a protein that in humans is encoded by the RAB2B gene.

References

  1. ↑ Dirac-Svejstrup AB, Sumizawa T, Pfeffer SR (February 1997). "Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI". The EMBO Journal. 16 (3): 465–72. doi:10.1093/emboj/16.3.465. PMC   1169650 . PMID   9034329.
  2. 1 2 Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra MC, Zerial M (November 1994). "Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes". EMBO J. 13 (22): 5262–73. doi:10.1002/j.1460-2075.1994.tb06860.x. PMC   395482 . PMID   7957092.
  3. 1 2 Nishimura N, Goji J, Nakamura H, Orita S, Takai Y, Sano K (November 1995). "Cloning of a brain-type isoform of human Rab GDI and its expression in human neuroblastoma cell lines and tumor specimens". Cancer Res. 55 (22): 5445–50. PMID   7585614.
  4. 1 2 3 Schalk I, Zeng K, Wu SK, Stura EA, Matteson J, Huang M, Tandon A, Wilson IA, Balch WE (May 1996). "Structure and mutational analysis of Rab GDP-dissociation inhibitor". Nature. 381 (6577): 42–8. Bibcode:1996Natur.381...42S. doi:10.1038/381042a0. PMID   8609986. S2CID   4249512.
This article incorporates text from the public domain Pfam and InterPro: IPR018203
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.