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.


METHODS
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.
Autiero
Ida
I
CRISCEB (Interdepartmental Research Center for Computational and Biotechnological Sciences) Second University of Naples, Naples, Italy.
Costantini
Susan
S
Colonna
Giovanni
G
D000465:Algorithms; D000495:Allosteric Site; D000595:Amino Acid Sequence; D003198:Computer Simulation; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D056564:Sirtuin 1; D037761:Sirtuins / Q000737:chemistry* / Q000502:physiology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology
D009687:Nuclear Proteins; C524448:RPS19BP1 protein, human; D014157:Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins