Abstract
Mutations of the alsin protein have been linked to infantile-onset ascending hereditary spastic paraplegia (IAHSP), a rare neurodegenerative disease. More precisely, the pathological R1611W mutation has been identified in the Vacuolar Protein Sorting 9 (VPS9) domain, which acts as a guanine nucleotide exchange factor (GEF) for Rab5. This mutation results in the expression of tryptophan instead of arginine that alters the oligomeric state of alsin and its GEF functions. Insights into the conformational structure of the wild-type or mutant VPS9 domain may help elucidate the mechanisms involved in the onset of the disease. In this study, we combined in vitro and in silico approaches to elucidate the structure and understand the effects of the R1611W mutation on the isolated VPS9 domain of alsin. This mutation induces conformational changes that alter the local structure of the protein and its ability to oligomerize. This study lays the groundwork for understanding how R1611W alters the VPS9 domain function.