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.