Mechanisms of Gasdermin Recognition by Proteases.

Autor: Liu Z; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States., Busscher BM; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States., Storl-Desmond M; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States., Xiao TS; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address: tsx@case.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2022 Feb 28; Vol. 434 (4), pp. 167274. Date of Electronic Publication: 2021 Sep 29.
DOI: 10.1016/j.jmb.2021.167274
Abstrakt: Members of the gasdermin family contain positively charged N-terminal domains (NTDs) capable of binding phospholipids and assembling membrane pores, and C-terminal domains (CTDs) that bind the NTDs to prevent pore formation in the resting states. The flexible NTD-CTD linker regions of gasdermins are highly variable in length and sequences, which may be attributable to gasdermin recognition by diverse proteases. In addition, protease cleavage within the NTDs is known to inactivate several gasdermin family members. Recognition and cleavage of the gasdermin family members by different proteases share common and distinct features at the protease active sites, as well as exosites recently identified for the inflammatory caspases. Utilization of exosites may strengthen enzyme-substrate interaction, improve efficiency of proteolysis, and enhance substrate selectivity. It remains to be determined if the dual site recognition of gasdermin D (GSDMD) by the inflammatory caspases is employed by other GSDMD-targeting proteases, or is involved in proteolytic processing of other gasdermins. Biochemical and structural approaches will be instrumental in revealing how potential exosites in diverse proteases engage different gasdermin substrates. Different features of gasdermin sequence, structure, expression characteristics, and post-translational modifications may dictate distinct mechanisms of protease-dependent activation or inactivation. Such diverse mechanisms may underlie the divergent physiological and pathological functions of gasdermins, and furnish opportunities for therapeutic targeting of gasdermins in infectious diseases and inflammatory disorders.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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