Human Sirt-1: Molecular Modeling and Structure-Function Relationships of an Unordered Protein

BACKGROUND Sirt-1 is a NAD+-dependent nuclear deacetylase of 747 residues that in mammals is involved in various important metabolic pathways, such as glucose metabolism and insulin secretion, and often works on many different metabolic substrates as a multifunctional protein. Sirt-1 down-regulates p53 activity, rising lifespan, and cell survival; it also deacetylases peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its coactivator 1 alpha (PGC-1alpha), promoting lipid mobilization, positively regulating insulin secretion, and increasing mitochondrial dimension and number. Therefore, it has been implicated in diseases such as diabetes and the metabolic syndrome and, also, in the mechanisms of longevity induced by calorie restriction. Its whole structure is not yet experimentally determined and the structural features of its allosteric site are unknown, and no information is known about the structural changes determined by the binding of its allosteric effectors. METHODOLOGY In this study, we modelled the whole three-dimensional structure of Sirt-1 and that of its endogenous activator, the nuclear protein AROS. Moreover, we modelled the Sirt-1/AROS complex in order to study the structural basis of its activation and regulation. CONCLUSIONS Amazingly, the structural data show that Sirt-1 is an unordered protein with a globular core and two large unordered structural regions at both termini, which play an important role in the protein-protein interaction. Moreover, we have found on Sirt-1 a conserved pharmacophore pocket of which we have discussed the implication.