PF01825

GPCR proteolysis site, GPS, motif

Pfam entry
Member databasePfam
Pfam typeconserved site
Short nameGPS
ClanGain
Author Bateman A;0000-0002-6982-4660
Sequence Ontology0001067

Description

The GPS motif is found in GPCRs, and is the site for auto-proteolysis, so is thus named, GPS
[4, 6, 3, 2]
. The GPS motif is a conserved sequence of ~40 amino acids containing canonical cysteine and tryptophan residues, and is the most highly conserved part of the domain. In most, if not all, cell-adhesion GPCRs these undergo autoproteolysis in the GPS between a conserved aliphatic residue (usually a leucine) and a threonine, serine, or cysteine residue
[1]
. In higher eukaryotes this motif is found embedded in the C-terminal beta-stranded part of a GAIN domain - GPCR-Autoproteolysis INducing (GAIN). The GAIN-GPS domain adopts a fold in which the GPS motif, at the C-terminus, forms five beta-strands that are tightly integrated into the overall GAIN domain. The GPS motif, evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. The GAIN-GPS domain is both necessary and sufficient functionally for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis
[5]
. In the cell-adhesion GPCRs and PKD proteins, the GPS motif is always located at the end of their long N-terminal extracellular regions, immediately before the first transmembrane helix of the respective protein.

References

1.Post-translational proteolytic processing of the calcium-independent receptor of alpha-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. Krasnoperov V, Lu Y, Buryanovsky L, Neubert TA, Ichtchenko K, Petrenko AG. J Biol Chem 277, 46518-26, (2002). PMID: 12270923

2.Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene. Wei W, Hackmann K, Xu H, Germino G, Qian F. J. Biol. Chem. 282, 21729-37, (2007). View articlePMID: 17525154

3.A latrophilin/CL-1-like GPS domain in polycystin-1. Ponting CP, Hofmann K, Bork P. Curr. Biol. 9, R585-8, (1999). View articlePMID: 10469603

4.Structural requirements for alpha-latrotoxin binding and alpha-latrotoxin-stimulated secretion. A study with calcium-independent receptor of alpha-latrotoxin (CIRL) deletion mutants. Krasnoperov V, Bittner MA, Holz RW, Chepurny O, Petrenko AG. J. Biol. Chem. 274, 3590-6, (1999). View articlePMID: 9920906

5.A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. Arac D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Sudhof TC, Brunger AT. EMBO J. 31, 1364-78, (2012). View articlePMID: 22333914

6.alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. Sugita S, Ichtchenko K, Khvotchev M, Sudhof TC. J. Biol. Chem. 273, 32715-24, (1998). View articlePMID: 9830014

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