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Beaufort, N.* ; Ingendahl, L.* ; Merdanovic, M.* ; Schmidt, A.* ; Podlesainski, D.* ; Richter, T.* ; Neumann, T.* ; Kuszner, M.* ; Vetter, I.R.* ; Stege, P.* ; Burston, S.G.* ; Filipovic, A.* ; Ruiz-Blanco, Y.B.* ; Bravo-Rodriguez, K.* ; Mieres-Perez, J.* ; Beuck, C.* ; Uebel, S.* ; Zobawa, M.* ; Schillinger, J.* ; Malik, R.* ; Todorov-Völgyi, K.* ; Rey, J.* ; Roberti, A.* ; Hagemeier, B.* ; Wefers, B. ; Müller, S.A.* ; Wurst, W. ; Sanchez-Garcia, E.* ; Zimmermann, A.* ; Hu, X.Y.* ; Clausen, T.* ; Huber, R.* ; Lichtenthaler, S.F.* ; Schmuck, C.* ; Giese, M.* ; Kaiser, M.* ; Ehrmann, M.* ; Dichgans, M.*

Rational correction of pathogenic conformational defects in HTRA1.

Nat. Commun. 15:5944 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 5944 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
DOI 10.1038/s41467-024-49982-8
Scopus ID 85198615105
PubMed ID 39013852
Erfassungsdatum 2024-07-18
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