Rational correction of pathogenic conformational defects in HTRA1

Nathalie Beaufort, Linda Ingendahl, Melisa Merdanovic, Andree Schmidt, David Podlesainski, Tim Richter, Thorben Neumann, Michael Kuszner, Ingrid R. Vetter, Patricia Stege, Steven G. Burston, Anto Filipovic, Yasser B. Ruiz-Blanco, Kenny Bravo-Rodriguez, Joel Mieres-Perez, Christine Beuck, Stephan Uebel, Monika Zobawa, Jasmin Schillinger, Rainer Malik, Katalin Todorov-Völgyi, Juliana Rey, Annabell Roberti, Birte Hagemeier, Benedikt Wefers, Stephan A. Müller, Wolfgang Wurst, Elsa Sanchez-Garcia, Alexander Zimmermann, Xiao-Yu Hu, Tim Clausen, Robert Huber, Stefan F. Lichtenthaler, Carsten Schmuck, Michael Giese, Markus Kaiser, Michael Ehrmann () and Martin Dichgans ()
Additional contact information
Nathalie Beaufort: Ludwig Maximilian University of Munich
Linda Ingendahl: University Duisburg-Essen
Melisa Merdanovic: University Duisburg-Essen
Andree Schmidt: German Center for Neurodegenerative Diseases (DZNE)
David Podlesainski: University Duisburg-Essen
Tim Richter: University Duisburg-Essen
Thorben Neumann: University Duisburg-Essen
Michael Kuszner: University Duisburg-Essen
Ingrid R. Vetter: Max-Planck-Institute of Molecular Physiology
Patricia Stege: Max-Planck-Institute of Molecular Physiology
Steven G. Burston: Biomedical Sciences Building
Anto Filipovic: University Duisburg-Essen
Yasser B. Ruiz-Blanco: University Duisburg-Essen
Kenny Bravo-Rodriguez: University Duisburg-Essen
Joel Mieres-Perez: University Duisburg-Essen
Christine Beuck: University Duisburg-Essen
Stephan Uebel: Max-Planck-Institute of Biochemistry
Monika Zobawa: Max-Planck-Institute of Biochemistry
Jasmin Schillinger: University Duisburg-Essen
Rainer Malik: Ludwig Maximilian University of Munich
Katalin Todorov-Völgyi: Ludwig Maximilian University of Munich
Juliana Rey: University Duisburg-Essen
Annabell Roberti: University Duisburg-Essen
Birte Hagemeier: University Duisburg-Essen
Benedikt Wefers: German Center for Neurodegenerative Diseases (DZNE)
Stephan A. Müller: German Center for Neurodegenerative Diseases (DZNE)
Wolfgang Wurst: German Center for Neurodegenerative Diseases (DZNE)
Elsa Sanchez-Garcia: Technical University Dortmund
Alexander Zimmermann: University Duisburg-Essen
Xiao-Yu Hu: Nanjing University of Aeronautics and Astronautics
Tim Clausen: Research Institute of Molecular Pathology (IMP)
Robert Huber: University Duisburg-Essen
Stefan F. Lichtenthaler: German Center for Neurodegenerative Diseases (DZNE)
Carsten Schmuck: University Duisburg-Essen
Michael Giese: University Duisburg-Essen
Markus Kaiser: University Duisburg-Essen
Michael Ehrmann: University Duisburg-Essen
Martin Dichgans: Ludwig Maximilian University of Munich

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49982-8

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DOI: 10.1038/s41467-024-49982-8

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