TY - JOUR
T1 - Structural insights into gene repression by the orphan nuclear receptor SHP
AU - Zhi, Xiaoyong
AU - Zhou, X. Edward
AU - He, Yuanzheng
AU - Zechner, Christoph
AU - Suino-Powell, Kelly M.
AU - Kliewer, Steven A.
AU - Melcher, Karsten
AU - Mangelsdorf, David J.
AU - Xu, H. Eric
PY - 2014
Y1 - 2014
N2 - Small heterodimer partner (SHP) is an orphan nuclear receptor thatfunctions as a transcriptional repressor to regulate bile acid andcholesterol homeostasis. Although the precise mechanism wherebySHP represses transcription is not known, E1A-like inhibitor ofdifferentiation (EID1) was isolated as a SHP-interacting protein andimplicated in SHP repression. Here we present the crystal structureof SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site nearthe C-terminal helix H12, the EID1-binding site is located at the Nterminus of the receptor, where EID1 mimics helix H1 of the nuclearreceptor ligand-binding domain. The residues composing the SHP-EID1 interface are highly conserved. Their mutation diminishesSHP-EID1 interactions and affects SHP repressor activity. Together,these results provide important structural insights into SHP co-factor recruitment and repressor function and reveal a conservedprotein interface that is likely to have broad implications fortranscriptional repression by orphan nuclear receptors.
AB - Small heterodimer partner (SHP) is an orphan nuclear receptor thatfunctions as a transcriptional repressor to regulate bile acid andcholesterol homeostasis. Although the precise mechanism wherebySHP represses transcription is not known, E1A-like inhibitor ofdifferentiation (EID1) was isolated as a SHP-interacting protein andimplicated in SHP repression. Here we present the crystal structureof SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site nearthe C-terminal helix H12, the EID1-binding site is located at the Nterminus of the receptor, where EID1 mimics helix H1 of the nuclearreceptor ligand-binding domain. The residues composing the SHP-EID1 interface are highly conserved. Their mutation diminishesSHP-EID1 interactions and affects SHP repressor activity. Together,these results provide important structural insights into SHP co-factor recruitment and repressor function and reveal a conservedprotein interface that is likely to have broad implications fortranscriptional repression by orphan nuclear receptors.
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U2 - 10.1073/pnas.1322827111
DO - 10.1073/pnas.1322827111
M3 - Article
C2 - 24379397
AN - SCOPUS:84892621275
SN - 0027-8424
VL - 111
SP - 839
EP - 844
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -