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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 2014|
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