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J Biol Chem, Vol. 274, Issue 16, 11086-11091, April 16, 1999

Complete Mapping of Divergent Amino Acids Responsible for Differential Ligand Binding of Folate Receptors  and

Karen M. Maziarz, Hugo L. Monaco, Feng Shen, and Manohar Ratnam

From the Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43614-5804 and the  Department of Genetics, University of Pavia, Via Abbiategrasso 207, 27100 Pavia, Italy

The folate receptor (FR) type  may be distinguished from FR- by its higher affinity for the circulating folate coenzyme, (6S)-5-methyltetrahydrofolate (5-CH₃H₄folate), and its opposite stereospecificity for reduced folate coenzymes. Previous studies showed that a single leucine to alanine substitution at position 49 of the mature protein sequence is responsible for the functional divergence of FR- (Shen, F., Zheng, X., Wang, H., and Ratnam, M. (1997) Biochemistry 36, 6157-6163); however, the results also indicated that the minimum requirement for conversion of FR- to the functional equivalent of FR- should include amino acid substitution(s) downstream of residue 92 in addition to mutation of L49A. To pinpoint those residues, chimeric FR-_L49A/FR- constructs including progressively shorter segments of FR- downstream of position 92 as well as selected point mutants were studied. Simultaneous substitution of Leu-49, Phe-104, and Gly-166 in FR- with the corresponding FR- residues Ala, Val, and Glu, respectively, reconstituted the ligand binding characteristics of FR-. The results also exclude a role for other residues in FR- in determining its functional divergence. A homology model of FR- based on the three-dimensional structure of the chicken riboflavin-binding protein is used to show the position of residues 49, 104, and 166 in relation to the hydrophobic cleft corresponding to the riboflavin-binding pocket.

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