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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
Creative Commons Lizenzvertrag
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
Corresponding Author
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
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)