An apparent dimerization motif in the third domain of alpha-fetoprotein: molecular mimicry of the steroid/thyroid nuclear receptor superfamily.
Alpha-fetoprotein (AFP) is a tumor-associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise 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 acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA-hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine-zipper dimerization (heptad) motif in the carboxy-terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, c-erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40-60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth-regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade.
Mizejewski
G J
GJ
Laboratory of Human Genetics, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509.
D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D012377:Rodentia; D017386:Sequence Homology, Amino Acid; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D000509:alpha-Fetoproteins