Structural basis for receptor recognition of vitamin-B12-intrinsic factor complexes
Structural basis for receptor recognition of vitamin-B12-intrinsic factor complexes
复制标题
DOI：
10.1038/nature08874
复制
发表时间：
2010-03-18
期刊：
影响因子：
64.8
通讯作者：
Andersen, Gregers R.
中科院分区：
文献类型：
--
作者：
Andersen, Christian Brix Folsted;Madsen, Mette;Andersen, Gregers R.
钴胺素（Cbl，维生素B-12）是一种细菌有机化合物，也是哺乳动物从饮食中摄取的必需辅酶。这通过胃内因子（IF）和回肠内吞cubam受体的联合作用发生，该受体由460千道尔顿（kDa）蛋白cubilin和45 kDa跨膜蛋白cubonless形成（1，2）。任何这些蛋白质的功能丧失最终导致人的Cbl缺乏症（3，4）。在这里，我们展示了在3.3埃分辨率下测定的IF-Cbl和cubilin IF-Cbl结合区（CUB 5 -8）（5）之间复合物的晶体结构。该结构提供了深入了解几个CUB（为'补体C1 r/C1 s，Uegf，Bmp 1'）结构域如何共同作为模块化配体结合区发挥作用，以及两个遥远的CUB结构域如何通过以Ca 2+依赖性方式结合两个IF结构域来拥抱Cbl分子。这一双点模型为Cbl如何间接诱导配体-受体偶联提供了可能的解释。最后，钙结合CUB域和低密度脂蛋白（LDL）受体A型模块的比较表明，静电配对的碱性配体精氨酸/赖氨酸残基与钙离子配位酸性谷氨酸/谷氨酸是一个共同的主题钙依赖性配体-受体相互作用。
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(1,2). Loss of function of any of these proteins ultimately leads to Cbl deficiency in man(3,4). Here we present the crystal structure of the complex between IF-Cbl and the cubilin IF-Cbl-binding-region (CUB5-8)(5) determined at 3.3 angstrom 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 Ca2+-dependent manner. This dual-point model provides a probable explanation of how Cbl indirectly induces ligand-receptor coupling. Finally, 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.