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J. Biol. Chem., Vol. 277, Issue 12, 9989-9996, March 22, 2002

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Comparative Analysis of Cobalamin Binding Kinetics and Ligand Protection for Intrinsic Factor, Transcobalamin, and Haptocorrin^*

Sergey N. Fedosov^§, Lars Berglund, Natalya U. Fedosova^¶, Ebba Nexø, and Torben E. Petersen

From the  Protein Chemistry Laboratory, Department of Molecular and Structural Biology, University of Aarhus, Science Park, Gustav Wieds Vej 10, 8000 Aarhus C, Denmark, the ^¶ Department of Biophysics, University of Aarhus, Ole Worms Alle 185, 8000 Aarhus C, Denmark, and the  Department of Clinical Biochemistry, AKH Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark

Changes in the absorbance spectrum of aquo-cobalamin (Cbl·OH₂) revealed that its binding to transcobalamin (TC) is followed by slow conformational reorganization of the protein-ligand complex (Fedosov, S. N., Fedosova, N. U., Nexø, E., and Petersen, T. E. (2000) J. Biol. Chem. 275, 11791-11798). Two phases were also observed for TC when interacting with a Cbl-analogue cobinamide (Cbi), but not with other cobalamins. The slow phase had no relation to the ligand recognition, since both Cbl and Cbi bound rapidly and in one step to intrinsic factor (IF) and haptocorrin (HC), namely the proteins with different Cbl specificity. Spectral transformations observed for TC in the slow phase were similar to those upon histidine complexation with Cbl·OH₂ and Cbi. In contrast to a closed structure of TC·Cbl·OH₂, the analogous IF and HC complexes revealed accessibility of Cbl's upper face to the external reagents. The binders decreased sensitivity of adenosyl-Cbl (Cbl·Ado) to light in the range: free ligand, IF·, HC·, TC·Cbl·Ado. The spectrum of TC·Cbl·Ado differed from those of IF and HC and mimicked Cbl·Ado participating in catalysis. The above data suggest presence of a histidine-containing cap shielding the Cbl-binding site in TC. The cap coordinates to certain corrinoids and, possibly, produces an incapsulated Ado-radical when Cbl·Ado is bound.

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