8TGP

Crystal structure of SIRT2 with FAM-PEG4-H4K16(myristoyl) peptide

8TGP の概要

• エントリーDOI: 10.2210/pdb8tgp/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-2, H4K16(myristoyl) peptide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: sirtuin sirtuin-2 sirt2, gene regulation, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38225.53

構造登録者

Nicely, N.I.,Weiser, B.P. (登録日: 2023-07-12, 公開日: 2024-01-24, 最終更新日: 2024-11-20)

主引用文献

Yang, J.,Nicely, N.I.,Weiser, B.P.
Effects of Dimerization on the Deacylase Activities of Human SIRT2.
Biochemistry, 62:3383-3395, 2023

PubMed Abstract: Human sirtuin isoform 2 (SIRT2) is an NAD-dependent enzyme that functions as a lysine deacetylase and defatty-acylase. Here, we report that SIRT2 readily dimerizes in solution and in cells and that dimerization affects its ability to remove different acyl modifications from substrates. Dimerization of recombinant SIRT2 was revealed with analytical size exclusion chromatography and chemical cross-linking. Dimerized SIRT2 dissociates into monomers upon binding long fatty acylated substrates (decanoyl-, dodecanoyl-, and myristoyl-lysine). However, we did not observe dissociation of dimeric SIRT2 in the presence of acetyl-lysine. Analysis of X-ray crystal structures led us to discover a SIRT2 double mutant (Q142A/E340A) that is impaired in its ability to dimerize, which was confirmed with chemical cross-linking and in cells with a split-GFP approach. In enzyme assays, the SIRT2(Q142A/E340A) mutant had normal defatty-acylase activity and impaired deacetylase activity compared with the wild-type protein. These results indicate that dimerization is essential for optimal SIRT2 function as a deacetylase. Moreover, we show that SIRT2 dimers can be dissociated by a deacetylase and defatty-acylase inhibitor, ascorbyl palmitate. Our finding that its oligomeric state can affect the acyl substrate selectivity of SIRT2 is a novel mode of activity regulation by the enzyme that can be altered genetically or pharmacologically.

PubMed: 37966275
DOI: 10.1021/acs.biochem.3c00381

実験手法

X-RAY DIFFRACTION (1.76 Å)