HNF4 was originally classified as an orphan receptor that exhibits constitutive transactivation activity apparently by being continuously bound to a variety of fatty acids. The existence of a ligand for HNF4 has been somewhat controversial, but linoleic acid (LA) has been identified as the endogenous ligand of native HNF4 expressed in mouse liver; the binding of LA to HNF4 is reversible.
The ligand binding domain of HNF4, as with other nuclear receptors, adopts a canonical alpha helical sandwich fold and interacts with co-activator proteins.
HNF4 binds to the consensus sequence AGGTCAaAGGTCA in order to activate transcription.
^Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (1994). "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver". Gene147 (2): 269–72. doi:10.1016/0378-1119(94)90079-5. PMID7926813.
^Wisely GB, Miller AB, Davis RG, Thornquest AD, Johnson R, Spitzer T, Sefler A, Shearer B, Moore JT, Miller AB, Willson TM, Williams SP (September 2002). "Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids". Structure10 (9): 1225–34. doi:10.1016/S0969-2126(02)00829-8. PMID12220494.
^Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE (October 2002). "Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand". J. Biol. Chem.277 (41): 37973–6. doi:10.1074/jbc.C200420200. PMID12193589.
^Duda K, Chi YI, Shoelson SE (May 2004). "Structural basis for HNF-4alpha activation by ligand and coactivator binding". J. Biol. Chem.279 (22): 23311–6. doi:10.1074/jbc.M400864200. PMID14982928.
^Fajans SS, Bell GI, Polonsky KS (2001). "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N Engl J Med345 (13): 971–80. doi:10.1056/NEJMra002168. PMID11575290.