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Journal Article

Structural insights into gene repression by the orphan nuclear receptor SHP

Xiaoyong Zhi, X. Edward Zhou, Yuanzheng He, Christoph Zechner, Kelly M. Suino-Powell, Steven A. Kliewer, Karsten Melcher, David J. Mangelsdorf and H. Eric Xu
Proceedings of the National Academy of Sciences of the United States of America
Vol. 111, No. 2 (January 14, 2014), pp. 839-844
Stable URL: http://www.jstor.org/stable/23770126
Page Count: 6
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Abstract

Small heterodimer partner (SHP) is an orphan nuclear receptor that functions as a transcriptional repressor to regulate bile acid and cholesterol homeostasis. Although the precise mechanism whereby SHP represses transcription is not known, E1A-like inhibitor of differentiation (EID1) was isolated as a SHP-interacting protein and implicated in SHP repression. Here we present the crystal structure of SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site near the C-terminal helix H12, the EID1-binding site is located at the N terminus of the receptor, where EID1 mimics helix H1 of the nuclear receptor ligand-binding domain. The residues composing the SHP—EID1 interface are highly conserved. Their mutation diminishes SHP—EID1 interactions and affects SHP repressor activity. Together, these results provide important structural insights into SHP cofactor recruitment and repressor function and reveal a conserved protein interface that is likely to have broad implications for transcriptional repression by orphan nuclear receptors.

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