Deota Shaunak, Chattopadhyay Tandrika, Ramachandran Deepti, Armstrong Eric, Camacho Beatriz, Maniyadath Babukrishna, Fulzele Amit, Gonzalez-de-Peredo Anne, Denu John M, Kolthur-Seetharam Ullas
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA.
Cell Rep. 2017 Mar 28;18(13):3069-3077. doi: 10.1016/j.celrep.2017.03.012.
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.
保守的NAD依赖性脱酰酶SIRT1在多种生理和病理生理条件下发挥着关键作用，有时甚至是相互矛盾的作用。在本研究中，我们发现了一种组织限制性的SIRT1亚型（SIRT1-ΔE2），它缺少外显子2（E2）。基于候选物的SIRT1底物筛选表明，该外显子编码的结构域在确定SIRT1蛋白-蛋白相互作用中起关键作用。SIRT1的E2结构域对于PGC1α结合、增强与p53的相互作用以及下游功能而言既必要又充分。由于发现SIRT1-FL和SIRT1-ΔE2具有相似的内在催化活性，我们提出E2结构域连接特定的底物蛋白。鉴于肝脏中不存在SIRT1-ΔE2，我们的研究结果为E2结构域在确定SIRT1-FL的“代谢功能”中的作用提供了见解。SIRT1-ΔE2和保守特异性结构域的鉴定将增进我们对SIRT1的理解，并指导治疗干预措施的开发。
