Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

Strutzenberg, Timothy S.; Zhu, Yingmin; Novick, Scott J.; Garcia-Ordonez, Ruben D.; Doebelin, Christelle; He, Yuanjun; Chang, Mi Ra; Kamenecka, Theodore M.; Edwards, Dean P.; Griffin, Patrick R.

doi:10.1016/j.jmb.2021.167258

Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

Journal Article · Mon Sep 20 00:00:00 EDT 2021 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2021.167258· OSTI ID:1981673

Strutzenberg, Timothy S. ^[1]; Zhu, Yingmin ^[2]; Novick, Scott J. ^[1]; Garcia-Ordonez, Ruben D. ^[1]; Doebelin, Christelle ^[1]; He, Yuanjun ^[1]; Chang, Mi Ra ^[1]; Kamenecka, Theodore M. ^[1]; Edwards, Dean P. ^[2]; Griffin, Patrick R. ^[1]

Scripps Research Inst., Jupiter, FL (United States)
Baylor Univ., Waco, TX (United States)

The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of RORγ is far from complete. Like most nuclear receptors, RORγ must recruit coregulatory protein to enact the RORγ target gene program. To date, a majority of structural studies have been focused exclusively on the RORγ ligand-binding domain and the ligand-dependent recruitment of small peptide segments of coregulators. Herein, we examine the ligand-dependent assembly of full length RORγ:coregulator complexes on cognate DNA response elements using structural proteomics and small angle x-ray scattering. The results from our studies suggest that RORγ becomes elongated upon DNA recognition, preventing long range interdomain crosstalk. We also determined that the DNA binding domain adopts a sequence-specific conformation, and that coregulatory protein may be able to ‘sense’ the ligand- and DNA-bound status of RORγ. We propose a model where ligand-dependent coregulator recruitment may be influenced by the sequence of the DNA to which RORγ is bound. Overall, the efforts described herein will illuminate important aspects of full length RORγ and monomeric orphan nuclear receptor target gene regulation through DNA-dependent conformational changes.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1981673

Journal Information:: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 22 Vol. 433; ISSN 0022-2836

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
HDX
RORγ
RORγt
XL-MS
biochemistry & molecular biology
integrative structural modeling
transcriptional coregulators

Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

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