Bianchetti Laurent, Sinar Deniz, Depenveiller Camille, Dejaegere Annick
Laboratoire de Chimie Biophysique de la Signalisation de la Transcription, Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique UMR7104, Illkirch, France.
Proteins. 2021 Mar 12. doi: 10.1002/prot.26073.
In vertebrates, the mineralocorticoid receptor (MR) is a steroid-activated nuclear receptor (NR) that plays essential roles in water-electrolyte balance and blood pressure homeostasis. It belongs to the group of oxo-steroidian NRs, together with the glucocorticoid (GR), progesterone (PR), and androgen (AR) receptors. Classically, these oxo-steroidian NRs homodimerize and bind to specific genomic sequences to activate gene expression. NRs are multi-domain proteins, and dimerization is mediated by both the DNA (DBD) and ligand binding domains (LBDs), with the latter thought to provide the largest dimerization interface. However, at the structural level, the dimerization of oxo-steroidian receptors LBDs has remained largely a matter of debate and, despite their sequence homology, there is currently no consensus on a common homodimer assembly across the four receptors, that is, GR, PR, AR, and MR. Here, we examined all available MR LBD crystals using different computational methods (protein common interface database, proteins, interfaces, structures and assemblies, protein-protein interaction prediction by structural matching, and evolutionary protein-protein interface classifier, and the molecular mechanics Poisson-Boltzmann surface area method). A consensus is reached by all methods and singles out an interface mediated by helices H9, H10 and the C-terminal F domain as having characteristics of a biologically relevant assembly. Interestingly, a similar assembly was previously identified for GRα, MR closest homolog. Alternative architectures that were proposed for GRα were not observed for MR. These data call for further experimental investigations of oxo-steroid dimer architectures.
在脊椎动物中，盐皮质激素受体（MR）是一种类固醇激活的核受体（NR），在水电解质平衡和血压稳态中发挥着重要作用。它与糖皮质激素（GR）、孕激素（PR）和雄激素（AR）受体同属于氧代类固醇核受体家族。传统上，这些氧代类固醇核受体形成同源二聚体并与特定的基因组序列结合以激活基因表达。核受体是多结构域蛋白，二聚化由DNA（DBD）和配体结合结构域（LBD）介导，后者被认为提供了最大的二聚化界面。然而，在结构层面，氧代类固醇受体LBD的二聚化在很大程度上仍存在争议，尽管它们具有序列同源性，但目前对于GR、PR、AR和MR这四种受体的共同同源二聚体组装尚无共识。在这里，我们使用不同的计算方法（蛋白质公共界面数据库、蛋白质、界面、结构和组装、通过结构匹配进行蛋白质-蛋白质相互作用预测、进化蛋白质-蛋白质界面分类器以及分子力学泊松-玻尔兹曼表面积方法）检查了所有可用的MR LBD晶体。所有方法都达成了共识，并确定了一个由螺旋H9、H10和C末端F结构域介导的界面，该界面具有生物学相关组装的特征。有趣的是，之前已为MR的最接近同源物GRα鉴定出了类似组装。未在MR中观察到先前为GRα提出的其他结构。这些数据呼吁对氧代类固醇二聚体结构进行进一步的实验研究。
