Mechanisms of Gasdermin Recognition by Proteases. Issue 4 (28th February 2022)

• Record Type: Journal Article
• Authors: Liu, Zhonghua; Busscher, Brianna M.; Storl-Desmond, Marta; Xiao, Tsan Sam
• Is Part Of: Journal of molecular biology. Volume 434:Issue 4(2022)
• Publication Date: 2022-02-28
• Subjects: gasdermin -- caspase -- exosite -- protease -- cleavage; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167274
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Flexible linkers connect pore-forming NTDs with autoinhibitory CTDs in gasdermins. Diverse proteases cleave gasdermin linkers or loops to regulate their activities. Exosites strengthen enzyme-substrate interactions and enhance substrate selectivities. Different features of gasdermin regulation by proteases underlie diverse functions. 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.