Apr 10, 1999

Complete mapping of divergent amino acids responsible for differential ligand binding of folate receptors alpha and beta

The Journal of Biological Chemistry
K M MaziarzM Ratnam

Abstract

The folate receptor (FR) type alpha may be distinguished from FR-beta 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-beta (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-beta to the functional equivalent of FR-alpha should include amino acid substitution(s) downstream of residue 92 in addition to mutation of L49A. To pinpoint those residues, chimeric FR-betaL49A/FR-alpha constructs including progressively shorter segments of FR-alpha downstream of position 92 as well as selected point mutants were studied. Simultaneous substitution of Leu-49, Phe-104, and Gly-166 in FR-beta with the corresponding FR-alpha residues Ala, Val, and Glu, respectively, reconstituted the ligand binding characteristics of FR-alpha. The results also exclude a role for other residues in FR-alpha in determining its functional divergence. A homology m...Continue Reading

Mentioned in this Paper

Folate Receptor 2
Peptide Mapping
Ligand Binding
5-methyltetrahydrofolate
Structure-Activity Relationship
Hormone Receptors, Cell Surface
Amino Acids, I.V. solution additive
Proteins, Recombinant DNA
Chimera Organism
Folate Receptor 1

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