title: Structural insights into gene repression by the orphan nuclear receptor SHP.
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.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhi
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: He
authors.forename: Christoph
authors.initials: C
authors.lastname: Zechner
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Suino-Powell
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003460:Crystallization; D015195:Drug Design; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry*
chemical_list: D001647:Bile Acids and Salts; D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099713:nuclear receptor subfamily 0, group B, member 2; D002784:Cholesterol