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

• Published in: Scientific reports Vol. 7; no. 1; pp. 14804 - 11
• Main Authors: Cabrera, Alvaro Cortes, Melo, Esther, Roth, Doris, Topp, Andreas, Delobel, Frederic, Stucki, Corinne, Chen, Chia-yi, Jakob, Peter, Banfai, Balazs, Dunkley, Tom, Schilling, Oliver, Huber, Sylwia, Iacone, Roberto, Petrone, Paula
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2017; Nature Publishing Group
• Subjects: 631/1647/2067; 631/45/173; 631/57/2266; Age; Allosteric properties; Allosteric Regulation; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Communication; Disease; Fibrils; Flexibility; High-Temperature Requirement A Serine Peptidase 1 - chemistry; High-Temperature Requirement A Serine Peptidase 1 - genetics; High-Temperature Requirement A Serine Peptidase 1 - metabolism; Humanities and Social Sciences; Humans; Macular degeneration; Monomers; multidisciplinary; Mutation; Peptides; Protein Domains; Protein folding; Protein Multimerization; Proteinase; Proteins; Proteolysis; Science; Science (multidisciplinary); Simulation; Structure-Activity Relationship; tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; Trimers; Tubulin; Tubulin - chemistry; Tubulin - genetics; Tubulin - metabolism; β-Amyloid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-14208-z

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.