1. HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication.
- Author
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Cabrera AC, Melo E, Roth D, Topp A, Delobel F, Stucki C, Chen CY, Jakob P, Banfai B, Dunkley T, Schilling O, Huber S, Iacone R, and Petrone P
- Subjects
- Allosteric Regulation, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, High-Temperature Requirement A Serine Peptidase 1 genetics, High-Temperature Requirement A Serine Peptidase 1 metabolism, Humans, Protein Domains, Structure-Activity Relationship, Tubulin chemistry, Tubulin genetics, Tubulin metabolism, tau Proteins chemistry, tau Proteins genetics, tau Proteins metabolism, High-Temperature Requirement A Serine Peptidase 1 chemistry, Protein Multimerization, Proteolysis
- 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.
- Published
- 2017
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