A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis

被引：333

作者：

Arac, Demet ^{[1
,2
,3
,4
,5
]}

Boucard, Antony A. ^{[2
]}

Bolliger, Marc F. ^{[2
]}

Nguyen, Jenna ^{[2
,3
,4
,5
]}

Soltis, S. Michael ^{[6
]}

Suedhof, Thomas C. ^{[2
]}

Brunger, Axel T. ^{[2
,3
,4
,5
]}

机构：

[1] Stanford Univ, Howard Hughes Med Inst, JH Clark Ctr, Stanford, CA 94305 USA

[2] Dept Mol & Cellular Physiol, Stanford, CA USA

[3] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA

[6] Stanford Univ, SLAC, Macromol Crystallog Grp, Stanford Synchrotron Radiat Lightsource, Stanford, CA 94305 USA

来源：

EMBO JOURNAL | 2012年 / 31卷 / 06期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

adhesion GPCRs; autoproteolysis; latrotoxin; polycystic kidney disease-1; synapse; PROTEIN-COUPLED RECEPTOR; ALPHA-LATROTOXIN RECEPTOR; CRYSTAL-STRUCTURE; PROTEOLYTIC SITE; TISSUE POLARITY; SECRETIN FAMILY; MEMBER; NEUREXINS; CLEAVAGE; GENE;

D O I：

10.1038/emboj.2012.26

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the similar to 40-residue GPS motif represents an integral part of a much larger similar to 320-residue domain that we termed GPCR-Autoproteolysis INducing (GAIN) domain. Crystal structures of GAIN domains from two distantly related cell-adhesion GPCRs revealed a conserved novel fold in which the GPS motif forms five beta-strands that are tightly integrated into the overall GAIN domain. The GAIN domain is 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. Functionally, the GAIN domain is both necessary and sufficient for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis. Thus, the GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases. The EMBO Journal (2012) 31, 1364-1378. doi:10.1038/emboj.2012.26; Published online 14 February 2012

引用

页码：1364 / 1378

页数：15

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