RT Journal Article
SR Electronic
T1 HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 163717
DO 10.1101/163717
A1 Alvaro Cortes Cabrera
A1 Esther Melo
A1 Doris Roth
A1 Andreas Topp
A1 Frederic Delobel
A1 Corinne Stucki
A1 Chia-yi Chen
A1 Peter Jakob
A1 Balazs Banfai
A1 Tom Dunkley
A1 Oliver Schilling
A1 Sylwia Huber
A1 Roberto Iacone
A1 Paula Petrone
YR 2017
UL http://biorxiv.org/content/early/2017/07/14/163717.abstract
AB 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. HtrA1 activation, although very relevant for drug-targeting this protease, remains poorly characterized. 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 oligomerization 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.HighlightsMonomeric HtrA1 is activated by a gating mechanism.Trimeric HtrA1 is regulated by PDZ-independent allosteric monomer cross-talk.HtrA1 oligomerization is key for proteolytic activity.Substrate-binding is precluded if monomers cannot communicate with each other.