结构蛋白质组学确定了黄体酮受体的顺序启动机制

Matthew D Mann, Min Wang, Josephine C Ferreon, Michael P Suess, Antrix Jain, Anna Malovannaya, Bruce D Pascal, Raj Kumar, Dean P Edwards, PATRICK R GRIFFIN
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引用次数: 0

摘要

孕酮受体(PR)是一种类固醇反应性核受体,以两种异构体形式表达:PR-A 和 PR-B。这两种异构体在生殖靶组织中显示出不同的表达模式和生物作用,PR-A:PR-B 信号的中断可能通过改变与致癌共调控蛋白(CoRs)的相互作用而与乳腺癌的发展有关。然而,人们对影响孕酮信号转导的同工酶特异性 PR-CoR 相互作用的分子细节仍然知之甚少。在本研究中,我们采用结构质谱法研究了纯化的全长 PR 和全长 CoR、类固醇受体辅激活因子 3(SRC3)和 p300 与靶 DNA 复合物的顺序结合机制。我们的发现揭示了 PR 与 CoR NR-box 的选择性结合,以及 PR、SRC3 和 p300 之间新的相互作用面,这些相互作用面在复合物组装过程中会发生变化。这为激活 PR 的顺序引物机制提供了一个结构模型。PR 与黄体酮激动剂和拮抗剂结合的比较挑战了核受体激活和抑制的经典模型。总之,我们从多肽水平透视了 PR 转录复合物的组织,并阐明了这些蛋白质在活性和非活性构象下的相互作用机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structural proteomics defines a sequential priming mechanism for the progesterone receptor
The progesterone receptor (PR) is a steroid-responsive nuclear receptor, expressed as two isoforms: PR-A and PR-B. The isoforms display distinct expression patterns and biological actions in reproductive target tissues and disruption of PR-A:PR-B signaling is associated with breast cancer development potentially by altering interactions with oncogenic co-regulatory protein (CoRs). However, the molecular details of isoform-specific PR-CoR interactions that influence progesterone signaling remain poorly understood. We employed structural mass spectrometry in this study to investigate the sequential binding mechanism of purified full-length PR and full-length CoRs, steroid receptor coactivator 3 (SRC3) and p300, as complexes with target DNA. Our findings reveal selective CoR NR-box binding by PR and novel interaction surfaces between PR, SRC3, and p300, which change during complex assembly. This provides a structural model for a sequential priming mechanism that activates PR. Comparisons of PR bound to progesterone agonist versus antagonist challenges the classical model of nuclear receptor activation and repression. Collectively, we offer a peptide-level perspective on the organization of the PR transcriptional complex and elucidate the mechanisms behind the interactions of these proteins, both in active and inactive conformations.
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