Abstract
Sirtuin belongs to a family of typical histone deacetylase which regulates the fundamental cellular biological processes including gene expression, genome stability, mitosis, nutrient metabolism, aging, mitochondrial function, and cell motility. Michael et. al. reported that B-site mutation (Q167A and H187A) decreased the SIRT2 activity but still the structural changes were not reported. Hence, we performed 5 ns molecular dynamics (MD) simulation on SIRT2 Apo-form and complexes with substrate/NAD+ and inhibitor of wild type (WT), Q167A, and H187A. The results revealed that the assembly and disassembly of C-site induced by presence of substrate/NAD+ and inhibitor, respectively. This assembly and disassembly was mainly due to the interaction between the substrate/NAD+ and inhibitor and F96 and the distance between F96 and H187 which are present at the neck of the C-site. MD simulations suggest that the conformational change of L3 plays a major role in assembly and disassembly of C-site. Our current results strongly suggest that the distinct conformational change of L3 as well as the assembly and disassembly of C-site plays an important role in SIRT2 deacetylation function. Our study unveiled the structural changes of SIRT2 in presence of NAD+ and inhibitor which should be helpful to improve the inhibitory potency of SIRT2.
Highlights
The posttranslational modification regulates a number of cellular processes including the modulation of DNA accessibility, replication and repair, acetylation and deacetylation of proteins
Four different classes of histone deacetylases (HDACs) have been identified in humans and ramifications into two groups based on its mechanism (i) the zinc-dependent or classical HDACs: HDAC 1, 2, 3 and 8 are homologues of reduced potassium dependency (Class I), Class II includes six subtypes and divided into two subclasses, class IIa (HDAC 4, 5, 7, 9) and Class IIb (HDAC 6,10) and HDAC 11 comes under Class IV (ii) the nicotinamide adenine dinucleotide (NAD+) dependent Sir2 proteins [2]
Recent studies find that SIRT2, a second member of the NAD+-dependent HDAC family, which is most widely known for its ability to interact with a-tubulin [14]
Summary
The posttranslational modification regulates a number of cellular processes including the modulation of DNA accessibility, replication and repair, acetylation and deacetylation of proteins. The HDACs and histone acetyltransferases (HATs) regulate the activity of non-histone protein targets such as p53 (deacetylated by HDAC1) [3,4] or a-tubulin (by HDAC6 and Sirt2) [5]. Seven distinct NAD+-dependent Sirtuin enzymes (SIRT1-7) were reported which are involved in the regulation of neuronal survival. The structure of SIRT2 catalytic domain consists of large and small domains The Zn binding domain consists of 3 antiparallel ß-sheets, one a-helix and Zn2+ was anchored by 4 conserved Cysteine residues (C195, C200, C221, and C224) in all classes of Sir2-like enzymes and the helical domain comprised of 4 helices, 2 short and 2 long helices. Small molecules that can modulate sirtuin activity have been shown to have potential in treating cancer [19,20], Parkinson’s disease [21], obesity and diabetes [22,23,24,25], aging and aging-related diseases [26] as well as it is a putative therapeutic target for affecting Huntington disease (HD) mediated transcriptional dysregualtions
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