ORCID: https://orcid.org/0000-0002-7088-4206; Ingendahl, Linda; Merdanovic, Melisa; Schmidt, Andree ORCID: https://orcid.org/0000-0002-8254-0777; Podlesainski, David ORCID: https://orcid.org/0000-0002-1111-8042; Richter, Tim ORCID: https://orcid.org/0009-0003-8310-6803; Neumann, Thorben; Kuszner, Michael; Vetter, Ingrid R.; Stege, Patricia; Burston, Steven G. ORCID: https://orcid.org/0000-0003-1848-1853; Filipovic, Anto; Ruiz-Blanco, Yasser B.; Bravo-Rodriguez, Kenny; Mieres-Perez, Joel ORCID: https://orcid.org/0000-0002-7875-0886; Beuck, Christine ORCID: https://orcid.org/0000-0001-7513-7384; Uebel, Stephan ORCID: https://orcid.org/0000-0002-3726-3942; Zobawa, Monika; Schillinger, Jasmin; Malik, Rainer ORCID: https://orcid.org/0000-0001-9212-2520; Todorov-Völgyi, Katalin ORCID: https://orcid.org/0009-0007-8073-9524; Rey, Juliana; Roberti, Annabell; Hagemeier, Birte; Wefers, Benedikt ORCID: https://orcid.org/0000-0002-2492-9389; Müller, Stephan A. ORCID: https://orcid.org/0000-0003-3414-307X; Wurst, Wolfgang ORCID: https://orcid.org/0000-0003-4422-7410; Sanchez-Garcia, Elsa; Zimmermann, Alexander; Hu, Xiao-Yu ORCID: https://orcid.org/0000-0002-9634-315X; Clausen, Tim ORCID: https://orcid.org/0000-0003-1582-6924; Huber, Robert; Lichtenthaler, Stefan F. ORCID: https://orcid.org/0000-0003-2211-2575; Schmuck, Carsten ORCID: https://orcid.org/0000-0001-6062-0357; Giese, Michael; Kaiser, Markus ORCID: https://orcid.org/0000-0002-6540-8520; Ehrmann, Michael ORCID: https://orcid.org/0000-0002-1927-260X und Dichgans, Martin ORCID: https://orcid.org/0000-0002-0654-387X
(2024):
Rational correction of pathogenic conformational defects in HTRA1.
In: Nature Communications, Vol. 15, 5944
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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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine > Munich Cluster for Systems Neurology (SyNergy) Medicine > Institute for Stroke and Dementia Research (ISD) |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-122961-5 |
| ISSN: | 2041-1723 |
| Language: | English |
| Item ID: | 122961 |
| Date Deposited: | 09. Dec 2024 07:15 |
| Last Modified: | 09. Dec 2024 07:15 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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