Title : Structural basis for universal corrinoid recognition by the cobalamin transport protein
haptocorrin
Abstract :
- Cobalamin ( Cbl ; vitamin B12 ) is an essential micronutrient synthesized only by bacteria
- Mammals have developed a sophisticated uptake system to capture the vitamin from the diet
- Cbl transport is mediated by three transport proteins : transcobalamin , intrinsic factor , and haptocorrin ( HC )
- All three proteins have a similar overall structure but a different selectivity for corrinoids
- Here, we present the crystal structures of human HC in complex with cyanocobalamin and cobinamide at 2.35 and 3.0 Å resolution, respectively
- The structures reveal that many of the interactions with the corrin ring are conserved among the human Cbl transporters
- However, the non-conserved residues Asn-120, Arg-357, and Asn-373 form distinct interactions allowing for stabilization of corrinoids other than Cbl
- A central binding motif forms interactions with the e- and f-side chains of the corrin ring and is conserved in corrinoid-binding proteins of other species
- In addition, the α- and β-domains of HC form several unique interdomain contacts and have a higher shape complementarity than those of intrinsic factor and transcobalamin
- The stabilization of ligands by all of these interactions is reflected in higher melting temperatures of the protein-ligand complexes
- Our structural analysis offers fundamental insights into the unique binding behavior of HC and completes the picture of Cbl interaction with its three transport proteins