Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.

ABSTRACT:

Background

Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity.

Results

Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead,

SUBMITTER: Gersing S 

PROVIDER: S-EPMC11021015 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature