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Mechanisms of Gasdermin Recognition by Proteases.

Authors
  • Liu, Zhonghua1
  • Busscher, Brianna M1
  • Storl-Desmond, Marta1
  • Xiao, Tsan Sam2
  • 1 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States. , (United States)
  • 2 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Journal of Molecular Biology
Publisher
Elsevier
Publication Date
Feb 28, 2022
Volume
434
Issue
4
Pages
167274–167274
Identifiers
DOI: 10.1016/j.jmb.2021.167274
PMID: 34599940
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2021 Elsevier Ltd. All rights reserved.

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