GoLoco motif

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GoLoco motif
PDB 1kjy EBI.jpg
crystal structure of human g[alpha]i1 bound to the goloco motif of rgs14
Identifiers
SymbolGoLoco
Pfam PF02188
InterPro IPR003109
SMART GoLoco
SCOP2 1kjy / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

GoLoco motif is a protein structural motif. [1] [2] [3] In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolyzing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to the receptor, GDP is displaced from G-alpha and GTP is bound. The GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP-bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see PDOC50132), and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators. [1] [4] acts as a GDI on G-alpha(i). [2] [5]

Contents

Structure

The crystal structure of the GoLoco motif in complex with G-alpha(i) has been solved. [6] It consists of three small alpha helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see PDOC50238). This addition of an arginine in the binding pocket affects the interaction of GDP with G-alpha and therefore is certainly important for the GoLoco GDI activity. [6]

Examples

Some proteins known to contain a GoLoco motif are listed below:

Human proteins containing this domain include:

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 P-loop "G domain", a protein domain common to many GTPases.

<span class="mw-page-title-main">G protein</span> Type of proteins

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

<span class="mw-page-title-main">Ras GTPase</span> GTP-binding proteins functioning on cell-cycle regulation

Ras, from "Rat sarcoma virus", is a family of related proteins that are 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 three-dimensional 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.

GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP's role in this function is to turn the G protein's activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> 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.

<span class="mw-page-title-main">Heterotrimeric G protein</span> Class of enzymes

Heterotrimeric G protein, also sometimes referred to as the "large" G proteins are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors, directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.

<span class="mw-page-title-main">G alpha subunit</span>

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

<span class="mw-page-title-main">GNAQ</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Together with GNA11, it functions as a Gq alpha subunit.

<span class="mw-page-title-main">GNAI1</span> Protein-coding gene in humans

Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.

<span class="mw-page-title-main">Regulator of G protein signaling</span>

Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.

<span class="mw-page-title-main">GNAO1</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(o) subunit alpha is a protein that in humans is encoded by the GNAO1 gene.

<span class="mw-page-title-main">AKAP13</span> Protein-coding gene in the species Homo sapiens

A-kinase anchor protein 13 is a protein that in humans is encoded by the AKAP13 gene. This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucleotide exchange factor (GEF) domain for the RhoA small GTP-binding protein.

<span class="mw-page-title-main">ARHGEF1</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene. This protein is also called RhoGEF1 or p115-RhoGEF.

<span class="mw-page-title-main">ARHGEF12</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene. This protein is also called RhoGEF12 or Leukemia-associated Rho guanine nucleotide exchange factor (LARG).

<span class="mw-page-title-main">RGS12</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 12 is a protein that in humans is encoded by the RGS12 gene.

<span class="mw-page-title-main">RGS14</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 14 (RGS14) is a protein that in humans is encoded by the RGS14 gene.

<span class="mw-page-title-main">GNA13</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein subunit alpha-13 is a protein that in humans is encoded by the GNA13 gene.

<span class="mw-page-title-main">GNAI3</span> Protein-coding gene in humans

Guanine nucleotide-binding protein G(k) subunit alpha is a protein that in humans is encoded by the GNAI3 gene.

<span class="mw-page-title-main">GNA12</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein subunit alpha-12 is a protein that in humans is encoded by the GNA12 gene.

References

  1. 1 2 Siderovski DP, Diversé-Pierluissi M, De Vries L (September 1999). "The GoLoco motif: a Galphai/o binding motif and potential guanine-nucleotide exchange factor". Trends Biochem. Sci. 24 (9): 340–1. doi:10.1016/s0968-0004(99)01441-3. PMID   10470031.
  2. 1 2 De Vries L, Fischer T, Tronchère H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG (December 2000). "Activator of G protein signaling 3 is a guanine dissociation inhibitor for Galpha i subunits". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14364–9. Bibcode:2000PNAS...9714364D. doi: 10.1073/pnas.97.26.14364 . PMC   18924 . PMID   11121039.
  3. ↑ Kimple RJ, Kimple ME, Betts L, Sondek J, Siderovski DP (April 2002). "Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits". Nature. 416 (6883): 878–81. Bibcode:2002Natur.416..878K. doi:10.1038/416878a. PMID   11976690. S2CID   4406208.
  4. ↑ Ponting CP (1999). "Raf-like Ras/Rap-binding domains in RGS12- and still-life-like signalling proteins". J. Mol. Med. 77 (10): 695–698. doi:10.1007/s001099900054. PMID   10606204. S2CID   22667367.
  5. ↑ Artemyev NO, Natochin M, Lester B, Peterson YK, Bernard ML, Lanier SM (2000). "AGS3 inhibits GDP dissociation from galpha subunits of the Gi family and rhodopsin-dependent activation of transducin". J. Biol. Chem. 275 (52): 40981–40985. doi: 10.1074/jbc.M006478200 . PMID   11024022.
  6. 1 2 Siderovski DP, Kimple RJ, Kimple ME, Betts L, Sondek J (2002). "Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits". Nature. 416 (6883): 878–881. Bibcode:2002Natur.416..878K. doi:10.1038/416878a. PMID   11976690. S2CID   4406208.
This article incorporates text from the public domain Pfam and InterPro: IPR003109


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