Structural Basis for Receptor Recognition of Vitamin B12-Intrinsic Factor Complexes

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    Vitamin B12 is a bacterial organic compound and an essential coenzyme in mammals, which take it up from the diet. This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460 kDa protein cubilin and the 45 kDa transmembrane protein amnionless. Loss of function of any of these proteins ultimately leads to vitamin B12 deficiency in man. We have determined the crystal structure of the complex between IF-B12 and the cubilin IF-B12-binding-region (CUB5-8) at 3.3 Å resolution. The structure provides insight into how several CUB (for 'complement C1r/C1s, Uegf, Bmp1') domains collectively function as modular ligand-binding regions, and how two distant CUB domains embrace vitamin B12 by binding the two IF domains in a Ca2+-dependent manner. This dual-point model provides a probable explanation of how vitamin B12 indirectly induces ligand-receptor coupling. In addition, the comparison of Ca2+-binding CUB domains and the low-density lipoprotein (LDL) receptor-type A modules suggests that the electrostatic pairing of a basic ligand arginine/lysine residue with Ca2+-coordinating acidic aspartates/glutamates is a common theme of Ca2+-dependent ligand-receptor interactions.

    Periode27 aug. 2010
    BegivenhedstitelBioStruct 2010
    BegivenhedstypeKonference
    ArrangørThe National Graduate school in Structural Biology
    PlaceringJægtvolden Fjordhotel, Trøndelag, NorgeVis på kort