Folding Simulations of a Nuclear Receptor Box-Containing Peptide Demonstrate the Structural Persistence of the LxxLL Motif Even in the Absence of Its Cognate Receptor

2017 ◽  
Vol 122 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Triantafyllia Adamidou ◽  
Konstantina-Olympia Arvaniti ◽  
Nicholas M. Glykos
Keyword(s):  
Nuclear Receptor ◽  
Cognate Receptor ◽  
Lxxll Motif ◽  
Folding Simulations

scholarly journals Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice

2007 ◽  
Vol 27 (23) ◽  
pp. 8073-8086 ◽  
Author(s):  
Qingtian Li ◽  
Mei-Jin Chu ◽  
Jianming Xu
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Bile Acid ◽  
Nuclear Receptor ◽  
Target Gene ◽  
Acid Synthesis ◽  
Estrogen Receptor Α ◽  
High Cholesterol Diet ◽  
Target Gene Expression ◽  
Lxxll Motif

ABSTRACT Although the LXXLL motif of nuclear receptor (NR) coactivators is essential for interaction with NRs, its role has not been assessed in unbiased animal models. The nuclear receptor coactivator 6 (NCoA6; also AIB3, PRIP, ASC-2, TRBP, RAP250, or NRC) is a coactivator containing an N-terminal LXXLL-1 (L1) and a C-terminal L2. L1 interacts with many NRs, while L2 interacts with the liver X receptor α (LXRα) and the estrogen receptor α (ERα). We generated mice in which L2 was mutated into AXXAL (L2m) to disrupt its interaction with LXRα and ERα. NCoA6L2m/L2m mice exhibited normal reproduction, mammary gland morphogenesis, and ERα target gene expression. In contrast, when treated with an LXRα agonist, lipogenesis and the LXRα target gene expression were significantly reduced in NCoA6L2m/L2m mice. The induction of Cyp7A1 expression by a high-cholesterol diet was impaired in NCoA6L2m/L2m mice, which reduced bile acid synthesis in the liver and excretion in the feces and resulted in cholesterol accumulation in the liver and blood. These results demonstrate that L2 plays a tissue- and NR-specific role: it is required for NCoA6 to mediate LXRα-regulated lipogenesis and cholesterol/bile acid homeostasis in the liver but not required for ERα function in the mammary gland.

scholarly journals Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors α and β

1999 ◽  
Vol 19 (12) ◽  
pp. 8226-8239 ◽  
Author(s):  
Ching-yi Chang ◽  
John D. Norris ◽  
Hanne Grøn ◽  
Lisa A. Paige ◽  
Paul T. Hamilton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Estrogen Receptor Alpha ◽  
Binding Pocket ◽  
Target Cells ◽  
Dependent Manner ◽  
Interaction Patterns ◽  
Core Motif ◽  
The Core ◽  
Lxxll Motif

ABSTRACT Recruitment of transcriptional coactivators following ligand activation is a critical step in nuclear receptor-mediated target gene expression. Upon binding an agonist, the receptor undergoes a conformational change which facilitates the formation of a specific coactivator binding pocket within the carboxyl terminus of the receptor. This permits the α-helical LXXLL motif within some coactivators to interact with the nuclear receptors. Until recently, the LXXLL motif was thought to function solely as a docking module; however, it now appears that sequences flanking the core motif may play a role in determining receptor selectivity. To address this issue, we used a combinatorial phage display approach to evaluate the role of flanking sequences in influencing these interactions. We sampled more than 108 variations of the core LXXLL motif with estradiol-activated estrogen receptor alpha (ERα) as a target and found three different classes of peptides. All of these peptides interacted with ERα in an agonist-dependent manner and disrupted ERα-mediated transcriptional activity when introduced into target cells. Using a series of ERα-mutants, we found that these three classes of peptides showed different interaction patterns from each other, suggesting that not all LXXLL motifs are the same and that receptor binding selectivity can be achieved by altering sequences flanking the LXXLL core motif. Most notable in this regard was the discovery of a peptide which, when overexpressed in cells, selectively disrupted ERβ- but not ERα-mediated reporter gene expression. This novel ERβ-specific antagonist may be useful in identifying and characterizing the ERβ-regulated process in estradiol-responsive cells. In conclusion, using a combinatorial approach to define cofactor-receptor interactions, we have clearly been able to demonstrate that not all LXXLL motifs are functionally equivalent, a finding which suggests that it may be possible to target receptor-LXXLL interactions to develop receptor-specific antagonists.

scholarly journals Structural and Functional Organization of TRAP220, the TRAP/Mediator Subunit That Is Targeted by Nuclear Receptors

2004 ◽  
Vol 24 (18) ◽  
pp. 8244-8254 ◽  
Author(s):  
Sohail Malik ◽  
Mohamed Guermah ◽  
Chao-Xing Yuan ◽  
Weizhen Wu ◽  
Soichiro Yamamura ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Functional Organization ◽  
Critical Role ◽  
Mediator Complex ◽  
Lxxll Motif ◽  
Stable Association ◽  
Necessary And Sufficient

ABSTRACT The TRAP/Mediator complex serves as a coactivator for many transcriptional activators, including nuclear receptors such as the thyroid hormone receptor (TR) that targets the TRAP220 subunit. The critical but selective function of TRAP220 is evidenced by the embryonic lethal phenotype of Trap220 − / − mice and by the observation that Trap220 − / − fibroblasts (isolated before embryonic death) are impaired in specific nuclear receptor-dependent pathways. Here we have used a biochemical and genetic approach to understand the basis of specificity in TRAP220 function. We show that Trap220 − / − cells possess a TRAP/Mediator complex that is relatively intact and compromised in its ability to support TR-dependent, but not VP16-dependent, transcription in vitro. Transfection studies using TRAP220 mutants revealed that the N terminus of TRAP220 is necessary and sufficient for stable association with the TRAP/Mediator complex and, further, that TRAP220-dependent TR function in transfected cells requires both of the NR boxes that contain the LXXLL motif implicated in nuclear receptor binding. Similarly, an analysis of isolated TRAP/Mediator complexes with mutations in either or both of the two NR boxes confirmed a critical role for them in in vitro coactivator function. The implications of these observations are discussed in terms of our present understanding of coactivator function.

scholarly journals Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation

1998 ◽  
Vol 12 (21) ◽  
pp. 3357-3368 ◽  
Author(s):  
E. M. McInerney ◽  
D. W. Rose ◽  
S. E. Flynn ◽  
S. Westin ◽  
T.-M. Mullen ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Lxxll Motif
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