Abstract
The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Among these, HtrA1 is implicated in several cancers, cerebrovascular disease and age-related macular degeneration. Currently, HtrA1 activation is not fully characterized and relevant for drug-targeting this protease. Our work provides a mechanistic step-by-step description of HtrA1 activation and regulation. We report that the HtrA1 trimer is regulated by an allosteric mechanism by which monomers relay the activation signal to each other, in a PDZ-domain independent fashion. Notably, we show that inhibitor binding is precluded if HtrA1 monomers cannot communicate with each other. Our study establishes how HtrA1 trimerization plays a fundamental role in proteolytic activity. Moreover, it offers a structural explanation for HtrA1-defective pathologies as well as mechanistic insights into the degradation of complex extracellular fibrils such as tubulin, amyloid beta and tau that belong to the repertoire of HtrA1.
Highlights
The human protease family high-temperature requirement A (HtrA) is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes
In human HtrA1, activation has been previously suggested to be a process of allosteric remodelling[25]
This mechanism relies on the communication of the activation signal across contiguous monomers in the HtrA1 trimer
Summary
The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, and a key player in several cellular processes. Experiments with polymeric proteins[4] have shown that the PDZ domain, dispensable for proteolysis of small peptides, is still essential to correctly process more complex substrates Taken together, this information indicates that human HtrA1 might undertake a similar activation process to other members of the family[12], but in which the role of the PDZ domain would not be pivotal. Molecular dynamics (MD) simulations have been successfully applied to characterize molecular states leading to conformational change[13,14,15] We combined this tool with community analysis[16] to identify allosteric regions and to investigate the mechanisms leading to HtrA1 activation both at the monomer level and globally for the trimer. Our study provides structural explanation for HtrA1-related pathologies such as CARASIL and CSVD, and explains why trimeric architecture is critical to HtrA1 function
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