5fyq

Sirt2 in complex with a 13-mer trifluoroacetylated Ran peptideSirt2 in complex with a 13-mer trifluoroacetylated Ran peptide

Structural highlights

5fyq is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Sirtuins are NAD+ dependent lysine-deacylases, regulating a variety of cellular processes. The nuclear Sirt1, the cytosolic Sirt2 and the mitochondrial Sirt3 are robust deacetylases, whereas the other sirtuins have preferences for longer acylchains. Most previous studies investigated sirtuin-catalysed deacylation on peptide substrates only. We used the genetic code expansion concept to produce natively folded site-specifically lysine acetylated Sirt1-3 substrate proteins, namely Ran, p53, PEPCK1, MnSOD, CypD and Hsp10, and analysed the deacetylation reaction. Some acetylated proteins such as Ran, p53 and Hsp10 were robustly deacetylated by Sirt1-3. However, other reported sirtuin substrate proteins such as CypD, MnSOD and PEPCK1, were not deacetylated. Using a structural and functional approach, we describe the ability of Sirt1-3 to deacetylate two adjacent acetylated lysine residues. The dynamics of this process has implications for the lifetime of acetyl-modifications on di-lysine-acetylation sites and thus constitutes a new mechanism for the regulation of proteins by acetylation. Our studies support that, besides the primary sequence-context, the protein structure is a major determinant of sirtuin substrate specificity.

Insights into lysine-deacetylation of natively folded substrate proteins by sirtuins.,Knyphausen P, de Boor S, Kuhlmann N, Scislowski L, Extra A, Baldus L, Schacherl M, Baumann U, Neundorf I, Lammers M J Biol Chem. 2016 May 18. pii: jbc.M116.726307. PMID:27226597^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231
↑ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818
↑ Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783
↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028
↑ Knyphausen P, de Boor S, Kuhlmann N, Scislowski L, Extra A, Baldus L, Schacherl M, Baumann U, Neundorf I, Lammers M. Insights into lysine-deacetylation of natively folded substrate proteins by sirtuins. J Biol Chem. 2016 May 18. pii: jbc.M116.726307. PMID:27226597 doi:http://dx.doi.org/10.1074/jbc.M116.726307

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OCA

[1] North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231

[2] Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818

[3] Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783

[4] Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028

[5] Knyphausen P, de Boor S, Kuhlmann N, Scislowski L, Extra A, Baldus L, Schacherl M, Baumann U, Neundorf I, Lammers M. Insights into lysine-deacetylation of natively folded substrate proteins by sirtuins. J Biol Chem. 2016 May 18. pii: jbc.M116.726307. PMID:27226597 doi:http://dx.doi.org/10.1074/jbc.M116.726307

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