Abstract
Life at the cellular level depends on effective coordination between diverse processes. Here we uncover a novel cross-regulation between metabolism and translation through a 3.2 Å cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) bound to sirtuin-2 (SIRT2), an NAD (+) -dependent deacetylase. This interaction, naturally triggered by the NAD (+) metabolite ADP-ribose (ADPR), resembles substrate binding and block SIRT2's active site. Interestingly, SerRS acetylation is not required for this interaction. SIRT2 binding sterically and allosterically impedes tRNA binding to SerRS, lowering charged tRNA (Ser) level and protein synthesis activity. Key interaction residues in both proteins emerged simultaneously in vertebrates, suggesting co-evolution for cross-regulation. Given ADPR's accumulation under stress, the ADPR-induced SerRS/SIRT2 interaction likely serves as a cell-protective response.