Knyphausen, Philipp, de Boor, Susanne, Kuhlmann, Nora, Scislowski, Lukas, Extra, Antje, Baldus, Linda, Schacherl, Magdalena ORCID: 0000-0002-5478-2509, Baumann, Ulrich, Neundorf, Ines ORCID: 0000-0001-6450-3991 and Lammers, Michael ORCID: 0000-0003-4168-4640 (2016). Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins. J. Biol. Chem., 291 (28). S. 14677 - 14695. BETHESDA: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

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 acyl chains. Most previous studies investigated sirtuin-catalyzed deacylation on peptide substrates only. We used the genetic code expansion concept to produce natively folded, site-specific, and lysine-acetylated Sirt1-3 substrate proteins, namely Ras-related nuclear, p53, PEPCK1, superoxide dismutase, cyclophilin D, and Hsp10, and analyzed the deacetylation reaction. Some acetylated proteins such as Ras-related nuclear, p53, and Hsp10 were robustly deacetylated by Sirt1-3. However, other reported sirtuin substrate proteins such as cyclophilin D, superoxide dismutase, 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 have implications for the lifetime of acetyl modifications on di-lysine acetylation sites and thus constitute 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Knyphausen, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Boor, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuhlmann, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scislowski, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Extra, AntjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schacherl, MagdalenaUNSPECIFIEDorcid.org/0000-0002-5478-2509UNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neundorf, InesUNSPECIFIEDorcid.org/0000-0001-6450-3991UNSPECIFIED
Lammers, MichaelUNSPECIFIEDorcid.org/0000-0003-4168-4640UNSPECIFIED
URN: urn:nbn:de:hbz:38-270006
DOI: 10.1074/jbc.M116.726307
Journal or Publication Title: J. Biol. Chem.
Volume: 291
Number: 28
Page Range: S. 14677 - 14695
Date: 2016
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication: BETHESDA
ISSN: 1083-351X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
STRUCTURAL BASIS; SIRT3-MEDIATED DEACETYLATION; HISTONE DEACETYLASES; STRUCTURE VALIDATION; COREPRESSOR COMPLEX; DIFFRACTION DATA; TRANSGENIC MICE; DRUG TARGET; DNA-BINDING; ADP-RIBOSEMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27000

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