Human SIRT1 Multispecificity Is Modulated by Active-Site Vicinity Substitutions during Natural Evolution.

ABSTRACT: Many enzymes that catalyze protein post-translational modifications can specifically modify multiple target proteins. However, little is known regarding the molecular basis and evolution of multispecificity in these enzymes. Here, we used a combined bioinformatics and experimental approaches to investigate the evolution of multispecificity in the sirtuin-1 (SIRT1) deacetylase. Guided by bioinformatics analysis of SIRT1 orthologs and substrates, we identified and examined important amino acid substitutions that have occurred during the evolution of sirtuins in Metazoa and Fungi. We found that mutation of human SIRT1 at these positions, based on sirtuin orthologs from Fungi, could alter its substrate specificity. These substitutions lead to reduced activity toward K382 acetylated p53 protein

SUBMITTER: Hendler A 

PROVIDER: S-EPMC7826192 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature