Structural basis for HNF-4alpha activation by ligand and coactivator binding. J Biol Chem 2004 May 28;279(22):23311-6
Date
02/26/2004Pubmed ID
14982928DOI
10.1074/jbc.M400864200Scopus ID
2-s2.0-2542496085 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
In addition to suggesting that fatty acids are endogenous ligands, our recent crystal structure of HNF-4alpha showed an unusual degree of structural flexibility in the AF-2 domain (helix alpha12). Although every molecule contained a fatty acid within its ligand binding domain, one molecule in each homodimer was in an open inactive conformation with alpha12 fully extended and colinear with alpha10. By contrast, the second molecule in each homodimer was in a closed conformation with alpha12 folded against the body of the domain in what is widely considered to be the active state. This indicates that although ligand binding is necessary, it is not sufficient to induce an activating structural transition in HNF-4alpha as is commonly suggested to occur for nuclear receptors. To further assess potential mechanisms of activation, we have solved a structure of human HNF-4alpha bound to both fatty acid ligand and a coactivator sequence derived from SRC-1. The mode of coactivator binding is similar to that observed for other nuclear receptors, and in this case, all of the molecules adopt the closed active conformation. We conclude that for HNF-4alpha, coactivator rather than ligand binding locks the active conformation.
Author List
Duda K, Chi YI, Shoelson SEAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesDNA-Binding Proteins
Hepatocyte Nuclear Factor 4
Humans
Ligands
Models, Molecular
Phosphoproteins
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Structure-Activity Relationship
Transcription Factors
