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结构蛋白质组学为孕激素受体定义了一种顺序引发机制。

Structural proteomics defines a sequential priming mechanism for the progesterone receptor.

作者信息

Mann Matthew D, Wang Min, Ferreon Josephine C, Tsoi Phoebe S, Suess Michael P, Jain Antrix, Malovannaya Anna, Alvarez Roberto Vera, Pascal Bruce D, Kumar Raj, Edwards Dean P, Griffin Patrick R

机构信息

Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, La Jolla, CA, USA.

Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.

出版信息

Nat Commun. 2025 May 12;16(1):4403. doi: 10.1038/s41467-025-59458-y.

DOI:10.1038/s41467-025-59458-y
PMID:40355435
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12069617/
Abstract

The progesterone receptor (PR) is a steroid-responsive nuclear receptor with two isoforms: PR-A and PR-B. Disruption of PR-A:PR-B signaling is associated with breast cancer through interactions with oncogenic co-regulatory proteins (CoRs). However, molecular details of isoform-specific PR-CoR interactions remain poorly understood. Using structural mass spectrometry, we investigate the sequential binding mechanism of purified full-length PR and intact CoRs, steroid receptor coactivator 3 (SRC3) and p300, as complexes on target DNA. Our findings reveal selective CoR NR-box binding by PR and unique interaction surfaces between PR and CoRs during complex assembly, providing a structural basis for CoR sequential binding on PR. Antagonist-bound PR showed persistent CoR interactions, challenging the classical model of nuclear receptor activation and repression. In this work, we offer a peptide-level perspective on the organization of the PR transcriptional complex and infer the mechanisms behind the interactions of these proteins, both in active and inactive conformations.

摘要

孕激素受体（PR）是一种类固醇反应性核受体，有两种异构体：PR-A和PR-B。PR-A:PR-B信号通路的破坏通过与致癌性共调节蛋白（CoR）相互作用与乳腺癌相关。然而，异构体特异性PR-CoR相互作用的分子细节仍知之甚少。我们使用结构质谱法，研究纯化的全长PR与完整的CoR、类固醇受体共激活因子3（SRC3）和p300作为复合物在靶DNA上的顺序结合机制。我们的研究结果揭示了PR对CoR NR盒的选择性结合以及复合物组装过程中PR与CoR之间独特的相互作用表面，为CoR在PR上的顺序结合提供了结构基础。拮抗剂结合的PR显示出持续的CoR相互作用，对核受体激活和抑制的经典模型提出了挑战。在这项工作中，我们从肽水平的角度探讨了PR转录复合物的组织，并推断了这些蛋白质在活性和非活性构象下相互作用背后的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/2f489d8e2e47/41467_2025_59458_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/61c6a6855708/41467_2025_59458_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/f22206a487d8/41467_2025_59458_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/c968ca3336a0/41467_2025_59458_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/7fb345a7f1c2/41467_2025_59458_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/c1e9818bdbf3/41467_2025_59458_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/cb4ef7ac91dc/41467_2025_59458_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/4e3467d94424/41467_2025_59458_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/2f489d8e2e47/41467_2025_59458_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/61c6a6855708/41467_2025_59458_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/f22206a487d8/41467_2025_59458_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/c968ca3336a0/41467_2025_59458_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/7fb345a7f1c2/41467_2025_59458_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/c1e9818bdbf3/41467_2025_59458_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/cb4ef7ac91dc/41467_2025_59458_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/4e3467d94424/41467_2025_59458_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39d4/12069617/2f489d8e2e47/41467_2025_59458_Fig8_HTML.jpg

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本文引用的文献

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