Can we decode how genetic variations impact protein function? This study presents a comprehensive analysis of glucokinase (GCK) variants to understand the mechanistic basis of their effects on protein activity. Combining yeast growth-based assay with previous activity scores, researchers examine the abundance of 95% of GCK missense and nonsense variants. Their findings reveal that 43% of hypoactive variants also exhibit decreased cellular protein abundance. Variants with low abundance are concentrated in the large domain, while residues in the small domain are more tolerant to mutations. The authors also show that many variants in the small domain affect GCK conformational dynamics, essential for proper activity. This research identifies residues crucial for GCK metabolic stability and conformational dynamics, potentially paving the way for targeted modulation of GCK activity to affect glucose homeostasis.
Published in Genome Biology, this research aligns with the journal's focus on genomic variation and its functional consequences. By characterizing the mechanistic basis of GCK variant effects, the study contributes to the understanding of how genetics impacts metabolic stability and conformational dynamics. This paper's methodologies makes it relevant.