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P311, a novel intrinsically disordered protein, regulates adipocyte development.

ABSTRACT: Adipocyte development and adipose tissue expansion have many implications for human diseases, including obesity. Obesity is a debilitating disorder and a risk factor for metabolic disorders including insulin resistance and diabetes mellitus, due in part to an overabundance of adipocytes and adipocyte dysfunction. In recent years, obesity has become a global pandemic with approximately one-third of US adults classified as obese. Adipose tissue has recently been identified as a major metabolic organ, classified into white adipose tissue (WAT) and brown adipose tissue (BAT). Other than lifestyle modifications and invasive surgeries, only a very limited number of drugs are available to treat obesity and overweight. P311 has been shown to play a key role in blood pressure regulation, vascular contractility and tissue remodeling. Here we present a role for P311 in adipogenesis using a 3T3-L1 cell culture model. P311 expression is initiated with the induction of adipogenesis and increased during adipogenesis. This increase correlates with an increase in the expression of the key adipogenic transcriptional factors PPAR?2 and C/EBP?. In addition, siRNA-mediated P311 knockdown inhibits adipogenic differentiation in 3T3-L1 cells. Finally, P311 binds to the PPAR?2 promoter, implicating P311 mediates adipogenesis partly through PPAR? activation.

SUBMITTER: Nunez S

PROVIDER: S-EPMC6561663 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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P311, a novel intrinsically disordered protein, regulates adipocyte development.

Nunez Sha'Kayla S Young Corey C Adebayo Olayinka O Muppuru Kesavulu Muni KM Badri Kameswara Rao KR

Biochemical and biophysical research communications 20190527 1

Adipocyte development and adipose tissue expansion have many implications for human diseases, including obesity. Obesity is a debilitating disorder and a risk factor for metabolic disorders including insulin resistance and diabetes mellitus, due in part to an overabundance of adipocytes and adipocyte dysfunction. In recent years, obesity has become a global pandemic with approximately one-third of US adults classified as obese. Adipose tissue has recently been identified as a major metabolic org ...[more]

PMID: 31146912

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Project description:Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD:TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs.

Dataset Information

P311, a novel intrinsically disordered protein, regulates adipocyte development.

Publications

P311, a novel intrinsically disordered protein, regulates adipocyte development.

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