HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication

摘要: The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, a key player in several cellular processes. Among these, HtrA1 implicated cancers, cerebrovascular disease age-related macular degeneration. Currently, activation not fully characterized relevant drug-targeting this protease. Our work provides mechanistic step-by-step description of regulation. We report that the trimer regulated by an allosteric mechanism which monomers relay signal to each other, PDZ-domain independent fashion. Notably, we show inhibitor binding precluded if cannot communicate with other. study establishes how trimerization plays fundamental role proteolytic activity. Moreover, it offers structural explanation HtrA1-defective pathologies as well insights into degradation complex extracellular fibrils such tubulin, amyloid beta tau belong repertoire HtrA1.