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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

Griffin Patrick, Mann Matthew, Wang Min, Ferreon Josephine, Suess Michael, Jain Antrix, Malovannaya Anna, Alvarez Roberto Vera, Pascal Bruce, Kumar Raj, Edwards Dean

机构信息

UF Scripps Biomedical Research Institute.

Baylor College of Medicine.

出版信息

Res Sq. 2024 Nov 14:rs.3.rs-5199635. doi: 10.21203/rs.3.rs-5199635/v1.

DOI:10.21203/rs.3.rs-5199635/v1
PMID:39606477
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11601812/
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. Collectively, 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

孕酮受体（PR）是一种类固醇反应性核受体，有两种亚型：PR-A和PR-B。PR-A:PR-B信号传导的破坏通过与致癌性共调节蛋白（CoRs）相互作用与乳腺癌相关。然而，亚型特异性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CoRs、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框的选择性结合以及复合物组装过程中PR与CoRs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。总体而言，我们从肽水平的角度对PR转录复合物的组织进行了研究，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/406c/11601812/2a3a378b9fa7/nihpp-rs5199635v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/5a1b83a42987/nihpp-rs5199635v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/deaf034d12de/nihpp-rs5199635v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/2e537d2ff991/nihpp-rs5199635v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/3c37a192b4b7/nihpp-rs5199635v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/5a074f82b388/nihpp-rs5199635v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/2a3a378b9fa7/nihpp-rs5199635v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/5a1b83a42987/nihpp-rs5199635v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/cba61ec96c09/nihpp-rs5199635v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/d6541501fa69/nihpp-rs5199635v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/deaf034d12de/nihpp-rs5199635v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/2e537d2ff991/nihpp-rs5199635v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/3c37a192b4b7/nihpp-rs5199635v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/5a074f82b388/nihpp-rs5199635v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/406c/11601812/2a3a378b9fa7/nihpp-rs5199635v1-f0008.jpg

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A molecular toolbox to study progesterone receptor signaling.研究孕激素受体信号转导的分子工具包。
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All-in-One Pseudo-MS Method for the Analysis of Gas-Phase Cleavable Protein Crosslinking Reactions.用于气相可裂解蛋白质交联反应分析的一体化拟质谱法。
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Long-range gene regulation in hormone-dependent cancer.激素依赖性癌症的长程基因调控。
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Progesterone receptor isoform ratios influence the transcriptional activity of progestins via the progesterone receptor.孕激素受体异构体比例通过孕激素受体影响孕激素的转录活性。
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