|3kq4, resolution 3.30Å ()|
|Ligands:||, , , ,|
|Gene:||GIF, IFMH (Homo sapiens), CUBN, IFCR (Homo sapiens)|
Structure of Intrinsic Factor-Cobalamin bound to its receptor Cubilin
Cobalamin (Cbl, vitamin B(12)) 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-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless. Loss of function of any of these proteins ultimately leads to Cbl deficiency in man. Here we present the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB(5-8)) determined at 3.3 A 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 the Cbl molecule by binding the two IF domains in a Ca(2+)-dependent manner. This dual-point model provides a probable explanation of how Cbl indirectly induces ligand-receptor coupling. Finally, the comparison of Ca(2+)-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 Ca(2+)-coordinating acidic aspartates/glutamates is a common theme of Ca(2+)-dependent ligand-receptor interactions.
Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes., Andersen CB, Madsen M, Storm T, Moestrup SK, Andersen GR, Nature. 2010 Mar 18;464(7287):445-8. PMID:20237569
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[IF_HUMAN] Defects in GIF are the cause of hereditary intrinsic factor deficiency (IFD) [MIM:261000]; also known as congenital pernicious anemia. IFD is an autosomal recessive disorder characterized by megaloblastic anemia.
[IF_HUMAN] Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the GIF-cobalamin complex is internalized via receptor-mediated endocytosis.
About this Structure
- Andersen CB, Madsen M, Storm T, Moestrup SK, Andersen GR. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. Nature. 2010 Mar 18;464(7287):445-8. PMID:20237569 doi:10.1038/nature08874
- ↑ Tanner SM, Li Z, Perko JD, Oner C, Cetin M, Altay C, Yurtsever Z, David KL, Faivre L, Ismail EA, Grasbeck R, de la Chapelle A. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4130-3. Epub 2005 Feb 28. PMID:15738392 doi:0500517102