The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless
The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless
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DOI：
10.1182/blood-2003-08-2852
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发表时间：
2004-03-01
期刊：
影响因子：
20.3
通讯作者：
Moestrup, SK
中科院分区：
文献类型：
--
作者：
Fyfe, JC;Madsen, M;Moestrup, SK
Imerslund-Grasbeck综合征（I-GS，巨幼细胞贫血1）是一种常染色体隐性遗传疾病，其特征是肠道钴胺素（维生素B-12）吸收不良和蛋白尿。在编码上皮蛋白的两个基因中的任何一个中发现了I-GS引起的突变：cubilin和AMN。Cubilin识别内在因子（IF）-钴胺素和各种其他蛋白质分别在肠和肾中被内吞，而AMN的功能尚不清楚。在这里，我们表明，cubilin和AMN共定位在极化上皮细胞的内吞装置和copurify作为一个紧密的复合物在IF-钴胺素的亲和力和非变性凝胶过滤色谱。在表达AMN或截短的IF-钴胺素结合cubilin构建体的转染细胞中，两种蛋白质都不单独赋予配体内吞作用。在cubilin转染子中，cubilin在早期生物合成隔室中积累。然而，在细胞共转染AMN和cubilin结构，cubilin贩运到细胞表面和内涵体，和细胞表现出IF钴胺素内吞和溶酶体降解IF。这些数据表明，cubilin和AMN是一种新的cubilin/AMN（cubam）复合物的亚基，其中AMN结合到cubilin的氨基末端的第三个，并指导cubilin与其配体的亚细胞定位和内吞作用。因此，影响2种蛋白质中任一种的突变可能会废除cubam复合物的功能并导致IG-S。(C)2004年，美国血液学会。
Imerslund-Grasbeck syndrome (I-GS, megaloblastic anemia 1) is an autosomal recessive disorder characterized by intestinal cobalamin (vitamin B-12) malabsorption and proteinuria. I-GS-causing mutations are found in either of 2 genes encoding the epithelial proteins: cubilin and amnionless (AMN). Cubilin recognizes intrinsic factor (IF)-cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively, whereas the function of AMN is unknown. Here we show that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis. In cubilin transfectants, cubilin accumulated in early biosynthetic compartments. However, in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes, and the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF. These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause IG-S. (C) 2004 by The American Society of Hematology.