Zymogenic latency in an ∼250-million-year-old astacin metallopeptidase

Autor: Tibisay Guevara, Arturo Rodríguez-Banqueri, Walter Stöcker, Christoph Becker-Pauly, F. Xavier Gomis-Rüth
Přispěvatelé: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Fundació La Marató de TV3, German Research Foundation
Rok vydání: 2022
Předmět:
Zdroj: Acta crystallographica. Section D, Structural biology. 78(Pt 11)
ISSN: 2059-7983
Popis: The horseshoe crab Limulus polyphemus is one of few extant Limulus species, which date back to ∼250 million years ago under the conservation of a common Bauplan documented by fossil records. It possesses the only proteolytic blood-coagulation and innate immunity system outside vertebrates and is a model organism for the study of the evolution and function of peptidases. The astacins are a family of metallopeptidases that share a central ∼200-residue catalytic domain (CD), which is found in >1000 species across holozoans and, sporadically, bacteria. Here, the zymogen of an astacin from L. polyphemus was crystallized and its structure was solved. A 34-residue, mostly unstructured pro-peptide (PP) traverses, and thus blocks, the active-site cleft of the CD in the opposite direction to a substrate. A central `PP motif' (F35-E-G-D-I39) adopts a loop structure which positions Asp38 to bind the catalytic metal, replacing the solvent molecule required for catalysis in the mature enzyme according to an `aspartate-switch' mechanism. Maturation cleavage of the PP liberates the cleft and causes the rearrangement of an `activation segment'. Moreover, the mature N-terminus is repositioned to penetrate the CD moiety and is anchored to a buried `family-specific' glutamate. Overall, this mechanism of latency is reminiscent of that of the other three astacins with known zymogenic and mature structures, namely crayfish astacin, human meprin β and bacterial myroilysin, but each shows specific structural characteristics. Remarkably, myroilysin lacks the PP motif and employs a cysteine instead of the aspartate to block the catalytic metal.
This study was supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references PID2019-107725RG-I00 from MICIN/AEI/10.13039/ 501100011033 to FXG-R, TG and AR-B, 2017SGR3 and Fundacio´ La Marato´ de TV3 201815 to FXG-R, TG and AR-B). Further support was obtained from German funding bodies (grant SFB877, Project A9: ‘Proteolysis as a regulatory Event in Pathophysiology’ from the Deutsche Forschungsgemeinschaft to CB-P).
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje