title: Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity.
abstract: The conserved NAD+-dependent deacylase SIRT1 plays pivotal, sometimes contrasting, roles in diverse physiological and pathophysiological conditions. In this study, we uncover a tissue-restricted isoform of SIRT1 (SIRT1-ΔE2) that lacks exon 2 (E2). Candidate-based screening of SIRT1 substrates demonstrated that the domain encoded by this exon plays a key role in specifying SIRT1 protein-protein interactions. The E2 domain of SIRT1 was both necessary and sufficient for PGC1α binding, enhanced interaction with p53, and thus downstream functions. Since SIRT1-FL and SIRT1-ΔE2 were found to have similar intrinsic catalytic activities, we propose that the E2 domain tethers specific substrate proteins. Given the absence of SIRT1-ΔE2 in liver, our findings provide insight into the role of the E2 domain in specifying "metabolic functions" of SIRT1-FL. Identification of SIRT1-ΔE2 and the conserved specificity domain will enhance our understanding of SIRT1 and guide the development of therapeutic interventions.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Shaunak
authors.initials: S
authors.lastname: Deota
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Tandrika
authors.initials: T
authors.lastname: Chattopadhyay
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Ramachandran
authors.affiliation: Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Armstrong
authors.affiliation: Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Camacho
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Babukrishna
authors.initials: B
authors.lastname: Maniyadath
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France.
authors.forename: Amit
authors.initials: A
authors.lastname: Fulzele
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gonzalez-de-Peredo
authors.affiliation: Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India. Electronic address: ullas@tifr.res.in.
authors.forename: Ullas
authors.initials: U
authors.lastname: Kolthur-Seetharam
mesh_terms: D000818:Animals; D055162:Biocatalysis; D002417:Cattle; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011485:Protein Binding; D000072417:Protein Domains; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D056564:Sirtuin 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D050505:Mutant Proteins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D056564:Sirtuin 1
keywords: AKT; DNA damage; E2; PGC1α; PPARα; SIRT1; SIRT1-Δ; insulin signaling; isoform; p53; specificity domain; β-oxidation