Structures of the Wild-Type and S59L Mutant CHCHD10 ProteinsImportant in Amyotrophic Lateral Sclerosis-FrontotemporalDementia

The S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helixdomain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateralsclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this proteincontain intrinsically disordered regions, and their structural characterization has been facing challenges.Here, for thefirst time in the literature, we present the structural ensemble properties of the wild-type andS59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics.Even though available experiments suggested that the S59L mutation may not change the structure of theCHCHD10 protein, our structural analysis clearly shows that the structure of this protein is significantlyaffected by the S59L mutation. We present here the secondary structure components with theirabundances per residue, the tertiary structure properties, the free energy surfaces based on the radius ofgyration and end-to-end distance values, the Ramachandran plots, the quantity of intramolecularhydrogen bonds, and the principal component analysis results. These results may be crucial in designingmore efficient treatment for ALS and FTD diseases.

Automated summary

This study provides structural insights into the wild-type and S59L mutant form of CHCHD10 protein in an aqueous solution, revealing that the S59L mutation significantly affects the structure of the protein. These findings are crucial for the design of more efficient treatments for ALS and FTD diseases.