Structural proteomics defines a sequential priming mechanism for the progesterone receptor
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-C...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59458-y |
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| author | 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 R. Griffin |
| author_facet | 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 R. Griffin |
| author_sort | Matthew D. Mann |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f80e5a76dfc345a8aee2cb5b6122b45a |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f80e5a76dfc345a8aee2cb5b6122b45a2025-08-20T01:51:30ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-59458-yStructural proteomics defines a sequential priming mechanism for the progesterone receptorMatthew D. Mann0Min Wang1Josephine C. Ferreon2Phoebe S. Tsoi3Michael P. Suess4Antrix Jain5Anna Malovannaya6Roberto Vera Alvarez7Bruce D. Pascal8Raj Kumar9Dean P. Edwards10Patrick R. Griffin11Skaggs Graduate School of Chemical and Biological Sciences, Scripps ResearchDepartment of Molecular and Cellular Biology, Baylor College of MedicineVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineMass Spectrometry Proteomics Core Facility. Advanced Technology Cores, Baylor College of MedicineVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineOmics Informatics LLCOmics Informatics LLCDepartment of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, Touro UniversityDepartment of Molecular and Cellular Biology, Baylor College of MedicineSkaggs Graduate School of Chemical and Biological Sciences, Scripps ResearchAbstract 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.https://doi.org/10.1038/s41467-025-59458-y |
| spellingShingle | 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 R. Griffin Structural proteomics defines a sequential priming mechanism for the progesterone receptor Nature Communications |
| title | Structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| title_full | Structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| title_fullStr | Structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| title_full_unstemmed | Structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| title_short | Structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| title_sort | structural proteomics defines a sequential priming mechanism for the progesterone receptor |
| url | https://doi.org/10.1038/s41467-025-59458-y |
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