LMAN1 is a molecular chaperone for the secretion of coagulation factor VIII
LMAN1 is a molecular chaperone for the secretion of coagulation factor VIII
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DOI：
10.1046/j.1538-7836.2003.00415.x
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发表时间：
2003-11-01
影响因子：
10.4
通讯作者：
Kaufman, RJ
中科院分区：
文献类型：
--
作者：
Cunningham, MA;Pipe, SW;Kaufman, RJ
凝血因子（F）V和VIII的联合缺乏是一种罕见的常染色体隐性出血性疾病，由大多数受影响个体中的LMAN 1（以前称为ERGIC-53）无效表达引起。先前，已经证明了对于FV和FVIII的有效分泌需要ER和高尔基体之间的功能性LMAN 1循环途径（Moussalli等人，J Biol Chem 1999; 274：32569），然而，LMAN 1和其货物之间相互作用的分子性质没有被表征。利用来自转染的HeLa和COS-1细胞的LMAN 1和FVIII的免疫共沉淀，我们证明了LMAN 1和FVIII在体内的相互作用。这种相互作用通过密集位于FVIII B结构域内的高甘露糖含量天冬酰胺连接寡糖以及蛋白质-蛋白质相互作用介导。这些结果解释的基础上最近确定的碳水化合物识别结构域的LMAN 1的晶体结构。
Combined deficiency of both coagulation factors (F)V and VIII is a rare autosomal recessive bleeding disorder caused by null expression of LMAN1 (previously termed ERGIC-53) in a majority of affected individuals. Previously, a requirement for a functional LMAN1 cycling pathway between the ER and Golgi was demonstrated for efficient secretion of FV and FVIII (Moussalli et al. J Biol Chem 1999; 274: 32569), however, the molecular nature of the interaction between LMAN1 and its cargo was not characterized. Using coimmunoprecipitation of LMAN1 and FVIII from transfected HeLa and COS-1cells, we demonstrate an interaction between LMAN1 and FVIII in vivo. The interaction was mediated via high mannose-containing asparagine-linked oligosaccharides that are densely situated within the B domain of FVIII, as well as protein-protein interactions. These results are interpreted based on the recent determination of the crystal structure of the carbohydrate recognition domain of LMAN1.