A distinct concerted mechanism of structural dynamism defines activity of human serine protease HtrA3

摘要

Human HtrA3 (high-temperature requirement protease A3) is a trimeric multitasking pro-papoptotic serine protease associated with critical cellular functions and pathogenicity.Implicated in diseases including cancer and pre-eclampsia, its role as a tumor suppressorand potential therapeutic target cannot be ignored. Therefore, elucidating its mode ofactivation and regulatory switch becomes indispensable towards modulating its functionswith desired effects for disease intervention. Using computational, biochemical and bio-physical tools, we delineated the role of all domains, their combinations and the criticalphenylalanine residues in regulating HtrA3 activity, oligomerization and specificity. Ourfindings underline the crucial roles of the N-terminus as well as the PDZ domain in oligo-merization and formation of a catalytically competent enzyme, thus providing newinsights into its structure–function coordination. Our study also reports an intricateligand-induced allosteric switch, which redefines the existing hypothesis of HtrA3 activa-tion besides opening up avenues for modulating protease activity favorably through suit-able effector molecules.