AN APPARENT DIMERIZATION MOTIF IN THE 3RD DOMAIN OF ALPHA-FETOPROTEIN- MOLECULAR MIMICRY OF THE STEROID THYROID NUCLEAR RECEPTOR SUPERFAMILY

Alpha-fetoprotein (AFP)dagger is a tumor-associated fetal marker, asso ciated both with tumor growth and with birth defects. AFP, whose preci se function is unknown, has been classified as belonging to a protein superfamily together with albumin and vitamin D-binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty ac ids, estrogens, thyroid hormones and retinoic acids. The steroid/thyro id nuclear receptor superfamily of proteins has recently become a majo r focus of biomedical investigation regarding regulation of gene expre ssion. These receptors are thought to bind to DNA-hormone response ele ments (HRE) that affect growth, development, differentiation, reproduc tion and homeostasis. The HREs are known to share DNA sequences with t he various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine-zipper dimerization (heptad) mot if in the carboxy-terminal third domain of both rodent and human AFP i s postulated. The presence of nine such hydrophobic repeats in the thi rd domain of the AFP molecule mimics the heptad dimerization repeats f ound in the retinoic acid, thyroid, c-erbA and other members of the nu clear receptor superfamily. Computer analysis revealed that the most c onservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40-60% homo logy with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth-regulatory properties (both inhibi tion and enhancement) that have been ascribed to AFP in the last decad e.