Figure 1.

Genomic variability and putative posttranslational modifications of GSDMD. A, comparison of genetic constraint between classes of proteins. The genetic constraint of a gene can be represented as a Z score, calculated as a function of the number of variants in a protein found in the exome normalized to the length of the protein. Higher Z scores indicate high constraint and low variability, whereas negative Z scores indicate low constraint and high variability. Each bar represents a single gene. Innate immune-sensing systems show a much higher tolerance of variation relative to kinase and metabolic enzymes. Among cell death–associated pore-forming proteins, the gasdermin family of proteins is comparable with MLKL, the necroptotic pore forming protein. CDK, cyclin-dependent kinase; NRTK, nonreceptor tyrosine kinase; TRP, transient receptor potential; RLR, RIG-I–like receptor; TLR, Toll-like receptor; NOD, nucleotide-binding oligomerization domain–like (2). B, screening of single nucleotides found in the human population for sites of putative posttranslational modification or structural significance with further workup of candidate sites.