Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.

ABSTRACT: The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-encoding GBA1 gene cause the lysosomal storage disorder Gaucher disease, while heterozygous and homozygous mutations are the most frequent genetic risk factor for Parkinson's disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as molecular chaperones for GCase. We identify several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we group the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stability

SUBMITTER: Dal Maso T 

PROVIDER: S-EPMC12117155 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature