Regulation of SIRT2 Deacylase Activity Through Self-Dimerization.

Human sirtuins are a family of nicotinamide adenine dinucleotide (NAD )-dependent enzymes that are responsible for removing acyl modifications from lysine residues. The deacylase activity of sirtuin isoform-2 (SIRT2) is involved in the formation and proliferation of cancers and is thought to regulate the progression of neurodegenerative diseases. The acyl substrates of SIRT2 are chemically diverse and range from small acetyl modifications to much larger, fatty acyl groups such as myristoyl. Here, we show that recombinant SIRT2 self-associates to form dimers in a substrate-dependent manner that regulates its deacylase activities. SIRT2's K for self-association was determined to be 98 nM, which is within range of its cellular concentration. SIRT2 alone readily forms dimers, but the enzyme undergoes a transition to monomer when bound to myristoyl substrate. SIRT2's oligomeric transition from dimer to monomer upon myristoyl substrate binding slows its demyristoylase reaction by adding an additional step to its reaction mechanism. In contrast, SIRT2 appears to remain dimerized when performing its deacetylase reaction which enhances its activity. We propose that SIRT2 abundance in cells may regulate its oligomeric state and deacylation kinetics, and additionally, its oligomeric states may be pharmacologically targeted to modulate acyl substrate selectivity. Finally, sirtuin isoforms 3 and 6 (SIRT3 and SIRT6) do not oligomerize at concentrations relevant to cellular activity, indicating that this mode of regulation is not inherent to all human sirtuins.