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

View ORCID ProfileAlvaro Cortes Cabrera, Esther Melo, Doris Roth, Andreas Topp, Frederic Delobel, Corinne Stucki, Chia-yi Chen, Peter Jakob, Balazs Banfai, Tom Dunkley, Oliver Schilling, Sylwia Huber, Roberto Iacone, Paula Petrone
doi: https://doi.org/10.1101/163717
Alvaro Cortes Cabrera
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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  • ORCID record for Alvaro Cortes Cabrera
Esther Melo
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Doris Roth
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Andreas Topp
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Frederic Delobel
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Corinne Stucki
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Chia-yi Chen
2Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany.
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Peter Jakob
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Balazs Banfai
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
3Soladis GmbH, 4052 Basel, Switzerland.
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Tom Dunkley
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Oliver Schilling
2Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany.
4BIOSS Centre for Biological Signaling Studies, University of Freiburg, D-79104 Freiburg, Germany
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Sylwia Huber
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Roberto Iacone
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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Paula Petrone
1Pharma Research & Early Development (pRED). Roche Innovation Center Basel, Basel, Switzerland.
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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. 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.

Highlights

  • Monomeric 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.

Footnotes

  • ↵% Paula Petrone. Lead Contact. Address: ppetrone{at}fpmaragall.org. Barcelonabeta Brain Research Center, Fundacion Pascual Maragall. Carrer de Wellington, 30, 08005 Barcelona, Spain.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 14, 2017.
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HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication
Alvaro Cortes Cabrera, Esther Melo, Doris Roth, Andreas Topp, Frederic Delobel, Corinne Stucki, Chia-yi Chen, Peter Jakob, Balazs Banfai, Tom Dunkley, Oliver Schilling, Sylwia Huber, Roberto Iacone, Paula Petrone
bioRxiv 163717; doi: https://doi.org/10.1101/163717
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HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication
Alvaro Cortes Cabrera, Esther Melo, Doris Roth, Andreas Topp, Frederic Delobel, Corinne Stucki, Chia-yi Chen, Peter Jakob, Balazs Banfai, Tom Dunkley, Oliver Schilling, Sylwia Huber, Roberto Iacone, Paula Petrone
bioRxiv 163717; doi: https://doi.org/10.1101/163717

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