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Assembly of Nucleosomal Arrays from Recombinant Core Histones and Nucleosome Positioning DNA
Published on: September 11, 2013
Structural basis for HNF-4alpha activation by ligand and coactivator binding
Karen Duda1, Young-In Chi, Steven E Shoelson
1Joslin Diabetes Center & Department of Medicine, Harvard Medical School, Boston, Massachussets 02215, USA.
The Journal of Biological Chemistry
|February 26, 2004
Summary
Fatty acid binding alone does not activate HNF-4alpha. Instead, coactivator binding is crucial for locking the nuclear receptor into its active conformation, revealing new insights into gene regulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Hepatocyte Nuclear Factor-4alpha (HNF-4alpha) is a key nuclear receptor involved in gene regulation.
- Fatty acids are proposed as endogenous ligands for HNF-4alpha.
- The AF-2 domain of HNF-4alpha exhibits significant structural flexibility.
Purpose of the Study:
- To investigate the structural mechanisms of HNF-4alpha activation.
- To determine the role of ligand and coactivator binding in HNF-4alpha conformational changes.
- To elucidate the structural basis for HNF-4alpha's active state.
Main Methods:
- X-ray crystallography was used to determine the structures of HNF-4alpha.
- Structures were solved for HNF-4alpha bound to fatty acids and to fatty acids plus a coactivator peptide.
- Conformational analysis of the AF-2 domain (helix alpha12) was performed.
Main Results:
- HNF-4alpha structures revealed distinct open (inactive) and closed (active) conformations.
- Fatty acid binding alone resulted in one molecule per homodimer adopting an inactive conformation.
- HNF-4alpha bound to both fatty acid and coactivator adopted the closed, active conformation in all molecules.
Conclusions:
- Ligand binding to HNF-4alpha is necessary but not sufficient for inducing the active conformation.
- Coactivator binding, not ligand binding, is the critical factor that locks HNF-4alpha into its active state.
- This finding contrasts with common models of nuclear receptor activation.
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