Language
English
Publication Date
10-3-2024
Journal
bioRxiv
DOI
10.1101/2024.09.06.611729
PMID
39282295
PMCID
PMC11398526
PubMedCentral® Posted Date
10-3-2024
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.
Published Open-Access
yes
Recommended Citation
Mann, Matthew D; Wang, Min; Ferreon, Josephine C; et al., "Structural Proteomics Defines a Sequential Priming Mechanism for the Progesterone Receptor" (2024). Faculty, Staff and Students Publications. 8040.
https://digitalcommons.library.tmc.edu/baylor_docs/8040