Language

English

Publication Date

11-14-2024

Journal

Research Square

DOI

10.21203/rs.3.rs-5199635/v1

PMID

39606477

PMCID

PMC11601812

PubMedCentral® Posted Date

11-14-2024

PubMedCentral® Full Text Version

Pre-Print

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.

Keywords

Progesterone receptor, hydrogen-deuterium exchange, crosslinking, mass spectrometry, protein-protein interactions, nuclear receptors, transcriptional co-regulatory proteins

Published Open-Access

yes

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