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In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence.

ABSTRACT: 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) is a short-chain dehydrogenase/reductase (SDR) responsible for inactivating cortisol and preventing its binding to the mineralocorticoid receptor (MR). Nonfunctional mutations in HSD11B2, the gene encoding 11betaHSD2, cause the hypertensive syndrome of apparent mineralocorticoid excess (AME). Like other such Mendelian disorders, AME is rare but has nevertheless helped to illuminate principles fundamental to the regulation of blood pressure. Furthermore, polymorphisms in HSD11B2 have been associated with salt sensitivity, a major risk factor for cardiovascular mortality. It is therefore highly likely that sequence variation in HSD11B2, having subtle functional ramifications, will affect blood pressure in the wider population. In this study, a three-dimensional homology model of 11betaHSD2 was created and used to hypothesize the functional consequences in terms of protein structure of published mutations in HSD11B2. This approach underscored the strong genotype-phenotype correlation of AME: severe forms of the disease, associated with little in vivo enzyme activity, arise from mutations occurring in invariant alignment positions. These were predicted to exert gross structural changes in the protein. In contrast, those mutations causing a mild clinical phenotype were in less conserved regions of the protein that were predicted to be relatively more tolerant to substitution. Finally, a number of pathogenic mutations are shown to be associated with regions predicted to participate in dimer formation, and in protein stabilization, which may therefore suggest molecular mechanisms of disease.

SUBMITTER: Manning JR

PROVIDER: S-EPMC2929884 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence.

Manning Jonathan R JR Bailey Matthew A MA Soares Dinesh C DC Dunbar Donald R DR Mullins John J JJ

Physiological genomics 20100622 3

11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) is a short-chain dehydrogenase/reductase (SDR) responsible for inactivating cortisol and preventing its binding to the mineralocorticoid receptor (MR). Nonfunctional mutations in HSD11B2, the gene encoding 11betaHSD2, cause the hypertensive syndrome of apparent mineralocorticoid excess (AME). Like other such Mendelian disorders, AME is rare but has nevertheless helped to illuminate principles fundamental to the regulation of blood pressure. ...[more]

PMID: 20571110

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Project description:Cytoplasmic I?B proteins are primary regulators that interact with NF-?B subunits in the cytoplasm of unstimulated cells. Upon stimulation, these I?B proteins are rapidly degraded, thus allowing NF-?B to translocate into the nucleus and activate the transcription of genes encoding various immune mediators. Subsequent to translocation, nuclear I?B proteins play an important role in the regulation of NF-?B transcriptional activity by acting either as activators or inhibitors. To date, molecular basis for the binding of I?B?, I?B? and I?B? along with their partners is known; however, the activation and inhibition mechanism of the remaining I?B (I?BNS, I?B? and Bcl-3) proteins remains elusive. Moreover, even though I?B proteins are structurally similar, it is difficult to determine the exact specificities of I?B proteins towards their respective binding partners. The three-dimensional structures of I?BNS, I?B? and I?B? were modeled. Subsequently, we used an explicit solvent method to perform detailed molecular dynamic simulations of these proteins along with their known crystal structures (I?B?, I?B? and Bcl-3) in order to investigate the flexibility of the ankyrin repeat domains (ARDs). Furthermore, the refined models of I?BNS, I?B? and Bcl-3 were used for multiple protein-protein docking studies for the identification of I?BNS-p50/p50, I?B?-p50/p65 and Bcl-3-p50/p50 complexes in order to study the structural basis of their activation and inhibition. The docking experiments revealed that I?B? masked the nuclear localization signal (NLS) of the p50/p65 subunits, thereby preventing its translocation into the nucleus. For the Bcl-3- and I?BNS-p50/p50 complexes, the results show that Bcl-3 mediated transcription through its transactivation domain (TAD) while I?BNS inhibited transcription due to its lack of a TAD, which is consistent with biochemical studies. Additionally, the numbers of identified flexible residues were equal in number among all I?B proteins, although they were not conserved. This could be the primary reason for their binding partner specificities.

Dataset Information

In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence.

Publications

In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence.

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