DNA binding alters ARv7 dimer interactions

Author:

Özgün Fatma1ORCID,Kaya Zeynep1ORCID,Morova Tunç2,Geverts Bart3,Abraham Tsion E.3,Houtsmuller Adriaan B.34,van Royen Martin E.34ORCID,Lack Nathan A.125ORCID

Affiliation:

1. School of Medicine, Koç University, Istanbul 34450, Turkey

2. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada

3. Erasmus Optical Imaging Centre, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands

4. Department of Pathology, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands

5. Koç University Research Centre for Translational Medicine (KUTTAM), Koç University, Istanbul 34450, Turkey

Abstract

ABSTRACT Androgen receptor (AR) splice variants are proposed to be a potential driver of lethal castration-resistant prostate cancer. AR splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation anti-androgens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work, we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining fluorescence resonance energy transfer and fluorescence recovery after photobleaching, we demonstrate that these heterodimers undergo conformational changes following DNA binding, indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics, suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homodimer or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.

Funder

Türkiye Bilimsel ve Teknolojik Araştırma Kurumu

Publisher

The Company of Biologists

Subject

Cell Biology

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