Structural basis for receptor recognition of vitamin-B12–intrinsic factor complexes

Abstract

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 trypanosomal haem acquisition and susceptibility to the host innate immune system

“…The essential roles of Ser59 and Asp168 in T. congolense HpHbR can be explained by their coordination of Lys164, which may stabilize the position of Lys164 and promote its interaction with the haem 7-propionate side chain (Fig. 5b) 12 indirectly promotes interaction with cubilin by locking the intrinsic factor in a specific conformation that allows a dual-point interaction with cubilin 37 .…”

Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites

“…C1s-C1r-C1r-C1s was shown to bind C1q through 6 sites involving the two outer (Glu and Asp) Ca 2+ -coordinating residues of the CUB 1 domains of C1r and C1s and CUB 2 domain of C1r (14). In each case, these two residues coordinate Ca 2+ through a single carboxyl oxygen, with their free oxygen being exposed and available for mediating an electrostatic bond with a basic residue (14,15,19). Examples of such Ca 2+ -binding CUB domainmediated salt bridges have been provided by the X-ray structures of the cubilin-intrinsic factor complex (19) and of the MBL-MASP-1 contact region (20).…”

“…In each case, these two residues coordinate Ca 2+ through a single carboxyl oxygen, with their free oxygen being exposed and available for mediating an electrostatic bond with a basic residue (14,15,19). Examples of such Ca 2+ -binding CUB domainmediated salt bridges have been provided by the X-ray structures of the cubilin-intrinsic factor complex (19) and of the MBL-MASP-1 contact region (20). In both instances, each of the two outer acidic Ca 2+ ligand forms an electrostatic bond with a single basic (Lys or Arg) residue.…”

History of the therapy of pernicious anemia

“…Az élővilágban B 12 -(kobalamin) vitamint egyedül mikroorganizmusok állítanak elő, amelyek a növényevő álla-tokba jutva nagy mennyiségben termelnek B 12 -t. A B 12 felszívódásához és a szervezet sejtjeibe történő bejutá-sához több transzportfehérjére van szükség, amelyek homológ kobalamint megkötő, valamint receptort felismerő szekvenciát tartalmaznak [26,27,28]. A kobalamintranszport-fehérjék közül említést érdemel a genetikailag jól jellemzett transzkobalamin-I (haptocorin R-protein, R-faktor, TC-I), a gastric intrinsic factor (GIF) és a transzkobalamin-II (TC-II).…”

“…Ez a körforgalom -a többi vitamintól eltérően -elvileg hosszú időre biztosítja a szervezet kobalaminigényét (napi 2-3 μg.) Említésre méltó, hogy a szervezetbe jutott kobalamin 1-2%-a passzív diffúzió útján is felszívódhat [26,27].…”