Effects of the Jokela type of spinal muscular atrophy-relatedG66V mutation on the structural ensemble characteristics ofCHCHD10

Abstract

The G66V pathological variant of the coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), mitochondrial, plays a role in Jokela type spinalmuscular atrophy. The wild-type and G66V mutant-type CHCHD10 proteins containintrinsically disordered regions, and therefore, their structural ensemble studies havebeen experiencing difficulties using conventional tools. Here, we show our resultsregarding the first characterization of the structural ensemble characteristics of theG66V mutant form of CHCHD10 and the first comparison of these characteristicswith the structural ensemble properties of wild-type CHCHD10. We find that thestructural properties, potential of mean force surfaces, and principal component anal-ysis show stark differences between these two proteins. These results are importantfor a better pathology, biochemistry and structural biology understanding ofCHCHD10 and its G66V genetic variant and it is likely that these reported structuralproperties are important for designing more efficient treatments for the Jokela typeof spinal muscular atrophy disease.