This is a summary of N. Beaufort, L. Ingendahl, M. Merdanovic et al. (2024). Rational correction of pathogenic conformational defects in HTRA1. Published in Nature Communications. https://www.doi.org/10.1038/s41467-024-49982-8
The challenge
CARASIL is a rare, serious, and fatal hereditary disease that manifests itself as a disease of the small vessels of the brain and causes strokes. It is caused by genetic mutations that lead to a loss of function of the HTRA1 protein. The enzyme plays an important role in maintaining the balance in the extracellular matrix. If its function is impaired, it can cleave and break down fewer proteins, which eventually results in clinical manifestations. There is no cure for CARASIL: treatment is limited to managing patient symptoms. We, therefore, studied strategies to reverse the deleterious effects of HTRA1 mutations.
Our approach
In close collaboration with Michael Ehrmann’s lab at the University of Duisberg-Essen, we combined in vitro, in silico, and in vivo analyses to repair the assembly and catalytic function of mutant HTRA1. Pathogenic protein conformations resulting in loss of function are difficult to address by conventional pharmaceutical compounds. To correct the conformation and reconstitute the activity of mutant HTRA1, we devised three independent biologic and chemical biology approaches involving protein trans-complementation, supramolecular chemical ligands, and peptidic ligands. In each case, the repair mechanism relies on restoring the integrity of the activation domain: in the protein trans-complementation method, we targeted the R274Q mutation by a compensatory mutant protein that is supplied in trans, the supramolecular chemical ligands approach stabilizes active HTRA1 trimers, whereas the final method is based on a natural peptide that activates HTRA1 monomers.
Our findings
We established mechanistically distinct protein repair approaches to reverse the deleterious effects of mutations that interfere with the assembly and catalytic function of HRTA1.
The implications
Our findings exemplify the feasibility of rational strategies to correct pathogenic protein conformations and open perspectives for precision medicine.
Creating SyNergies
The study was led by Martin Dichgans, director of the Institute for Stroke and Dementia Research at LMU University Hospital in close collaboration with Michael Ehrmann’s lab at the University of Duisberg-Essen. This study greatly benefited from collaborations within the SyNergy cluster and from the technology offered.
