Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl recognition and regulation features

• DOI: 10.1038/s41467-017-01701-2
• Publication Date: 2017-11-09T14:24:56Z
• Authors: Martin Pannek; Zeljko Simic; Matthew Fuszard; Marat Meleshin; Dante Rotili; Antonello Mai; Mike Schutkowski; Clemens Steegborn
• Keywords: SIRT3

Sirtuins are evolutionary conserved NAD+-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria regulates fatty acid apoptosis. In contrast the mitochondrial deacetylase Sirt3 desuccinylase Sirt5, no prominent deacylase activity structural information available Sirt4. Here we describe acyl substrates crystal structures enzyme shows isoform-specific selectivity, with significant against hydroxymethylglutarylation. Crystal of from Xenopus tropicalis reveal a particular binding site an additional access channel, rationalizing its activities. further identify conserved, loop that folds into active potentially catalysis. Using these results, establish efficient assays, unusual regulation by NADH, effects pharmacological modulators.