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Structural proteomics defines a sequential priming mechanism for the progesterone receptor

Author

Listed:
  • Matthew D. Mann

    (Scripps Research
    The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Min Wang

    (Baylor College of Medicine)

  • Josephine C. Ferreon

    (Baylor College of Medicine)

  • Phoebe S. Tsoi

    (Baylor College of Medicine)

  • Michael P. Suess

    (Baylor College of Medicine)

  • Antrix Jain

    (Baylor College of Medicine)

  • Anna Malovannaya

    (Baylor College of Medicine)

  • Roberto Vera Alvarez

    (Omics Informatics LLC)

  • Bruce D. Pascal

    (Omics Informatics LLC)

  • Raj Kumar

    (Touro University)

  • Dean P. Edwards

    (Baylor College of Medicine)

  • Patrick R. Griffin

    (Scripps Research
    The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

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.

Suggested Citation

  • Matthew D. Mann & Min Wang & Josephine C. Ferreon & Phoebe S. Tsoi & Michael P. Suess & Antrix Jain & Anna Malovannaya & Roberto Vera Alvarez & Bruce D. Pascal & Raj Kumar & Dean P. Edwards & Patrick , 2025. "Structural proteomics defines a sequential priming mechanism for the progesterone receptor," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59458-y
    DOI: 10.1038/s41467-025-59458-y
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