Identification of amino acid residues that determine the differential ligand specificities of folate receptors alpha and beta

Biochemistry
F ShenM Ratnam

Abstract

The homologous folate receptor (FR) types alpha and beta from both human and murine sources have opposite stereospecificities for reduced folate coenzymes and different affinities for a variety of (anti)folate compounds. The present study identifies the critical amino acid sequence divergence underlying functional differences between FR-alpha and FR-beta. Chimeric constructs of the cDNAs encoding human FR-alpha and FR-beta were expressed in human 293 fibroblasts. The resulting membrane associated proteins were characterized in terms of their ability to bind [3H]folic acid and their relative affinities for the (6S) and (6R) diastereoisomers of N5-methyltetrahydrofolate. Substitution of the amino-terminal portion (residues 1-92) in the mature FR-alpha polypeptide with the corresponding segment of FR-beta resulted in folate binding characteristics similar to FR-beta. Next, a series of chimeric constructs were generated, involving substitution of progressively shorter segments within residues 1-92 in FR-alpha with the corresponding peptides of FR-beta. In this fashion, it was determined that the alanine residue at position 49 in FR-alpha was critical for its functional divergence from FR-beta, since substitution at this position wi...Continue Reading

References

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Citations

Apr 20, 2004·Advanced Drug Delivery Reviews·Hala Elnakat, Manohar Ratnam
Apr 20, 2004·Advanced Drug Delivery Reviews·Chun-Yen KeMark A Green
Dec 31, 2003·Nuclear Medicine and Biology·Chun-Yen KeMark A Green
Nov 22, 2005·Expert Opinion on Drug Delivery·Xiaogang Pan, Robert J Lee
Jul 2, 2003·Expert Opinion on Biological Therapy·Manohar RatnamXing Pan
Mar 17, 1999·Journal of Chemotherapy·T M Trippett, J R Bertino
Dec 17, 2014·Journal of Translational Medicine·Katarzyna UrbanskaDaniel J Powell

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