Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner.
The functional interaction between the orphan nuclear receptors small heterodimer partner (SHP) and liver receptor homolog 1 (LRH-1), where SHP binds to LRH-1 and represses its constitutive transcriptional activity, is crucial for regulating genes involved in cholesterol homeostasis. Here, we report structural and biochemical analyses of the LRH-1/SHP interaction. The crystal structure and modeling studies of the LRH-1 ligand-binding domain bound to either of the two LXXLL-related motifs of SHP show that the receptor undergoes conformational changes to accommodate the SHP docking and reveal key residues that determine the potency and selectivity of SHP binding. Through a combination of mutagenesis and binding studies, we demonstrate that only the second SHP LXXLL motif is required for repressing LRH-1, and this motif displays a strong preference for binding to LRH-1 over the closely related receptor steroidogeneic factor 1 (SF-1). Structural comparisons indicate that this binding selectivity is determined by residues flanking the core LXXLL motifs. These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved.
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
Yong
Y
Li
Mihwa
M
Choi
Kelly
K
Suino
Amanda
A
Kovach
Jennifer
J
Daugherty
Steven A
SA
Kliewer
H Eric
HE
Xu
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003461:Crystallography; D005786:Gene Expression Regulation / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D002784:Cholesterol