NMR-identification of the interaction between BRCA1 and the intrinsically disordered monomer of the Myc-associated factor X

Author(s)

Ludovica Martina Epasto, Christopher Pötzl, Herwig Peterlik, Mahdi Khalil, Christine Saint-Pierre, Didier Gasparutto, Giuseppe Sicoli, Dennis Kurzbach

Abstract

The breast cancer susceptibility 1 (BRCA1) protein plays a pivotal role in modulating the transcriptional activity of the vital intrinsically disordered transcription factor MYC. In this regard, mutations of BRCA1 and interruption of its regulatory activity are related to hereditary breast and ovarian cancer (HBOC). Interestingly, so far, MYC's main dimerization partner MAX (MYC-associated factor X) has not been found to bind BRCA1 despite a high sequence similarity between both oncoproteins. Herein, we show that a potential reason for this discrepancy is the heterogeneous conformational space of MAX, which encloses a well-documented folded coiled-coil homodimer as well as a less common intrinsically disordered monomer state—contrary to MYC, which exists mostly as intrinsically disordered protein in the absence of any binding partner. We show that when the intrinsically disordered state of MAX is artificially overpopulated, the binding of MAX to BRCA1 can readily be observed. We characterize this interaction by nuclear magnetic resonance (NMR) spectroscopy chemical shift and relaxation measurements, complemented with ITC and SAXS data. Our results suggest that BRCA1 directly binds the MAX monomer to form a disordered complex. Though probed herein under biomimetic in-vitro conditions, this finding can potentially stimulate new perspectives on the regulatory network around BRCA1 and its involvement in MYC:MAX regulation.

Organisation(s)

Department of Biological Chemistry, Dynamics of Condensed Systems, NMR Centre

External organisation(s)

University of Lille, University of Grenoble Alpes

Journal

Protein Science

Volume

33

ISSN

0961-8368

DOI

https://doi.org/10.1002/pro.4849

Publication date

01-2024

Peer reviewed

Yes

Austrian Fields of Science 2012

106002 Biochemistry, 106023 Molecular biology

Keywords

ASJC Scopus subject areas

Biochemistry, Molecular Biology

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Portal url

https://ucris.univie.ac.at/portal/en/publications/nmridentification-of-the-interaction-between-brca1-and-the-intrinsically-disordered-monomer-of-the-mycassociated-factor-x(6da2b0aa-0a24-4a08-8825-40e351a0d336).html