Li Chaoyang, Wong Poki, Pan Tao, Xiao Fan, Yin Shaoman, Chang Binggong, Kang Shin-Chung, Ironside James, Sy Man-Sun
Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44107-1712, U.S.A.
Biochem J. 2007 Sep 1;406(2):333-41. doi: 10.1042/BJ20061857.
The normal PrP(C) (cellular prion protein) contains sLe(X) [sialyl-Le(X) (Lewis X)] and Le(X). sLe(X) is a ligand of selectins. To examine whether PrP(C) is a ligand of selectins, we generated three human PrP(C)-Ig fusion proteins: one with Le(X), one with sLe(X), and the other with neither Le(X) nor sLe(X). Only Le(X)-PrP(C)-Ig binds E-, L- and P-selectins. Binding is Ca(2+)-dependent and occurs with nanomolar affinity. Removal of sialic acid on sLe(X)-PrP(C)-Ig enables the fusion protein to bind all selectins. These findings were confirmed with brain-derived PrP(C). The selectins precipitated PrP(C) in human brain in a Ca(2+)-dependent manner. Treatment of brain homogenates with neuraminidase increased the amounts of PrP(C) precipitated. Therefore the presence of sialic acid prevents the binding of PrP(C) in human brain to selectins. Hence, human brain PrP(C) interacts with selectins in a manner that is distinct from interactions in peripheral tissues. Alternations in these interactions may have pathological consequences.
正常的朊蛋白(C)(细胞朊蛋白)含有唾液酸化路易斯X [sialyl-Le(X) (路易斯X)]和路易斯X。唾液酸化路易斯X是选择素的配体。为了研究朊蛋白(C)是否为选择素的配体,我们制备了三种人朊蛋白(C)-免疫球蛋白融合蛋白:一种带有路易斯X,一种带有唾液酸化路易斯X,另一种既不带有路易斯X也不带有唾液酸化路易斯X。只有带有路易斯X的朊蛋白(C)-免疫球蛋白能结合E-选择素、L-选择素和P-选择素。这种结合依赖于钙离子,且以纳摩尔亲和力发生。去除唾液酸化路易斯X-朊蛋白(C)-免疫球蛋白上的唾液酸能使该融合蛋白结合所有选择素。这些发现通过脑源性朊蛋白(C)得到了证实。选择素能以钙离子依赖的方式沉淀人脑中的朊蛋白(C)。用神经氨酸酶处理脑匀浆会增加沉淀的朊蛋白(C)的量。因此,唾液酸的存在会阻止人脑中的朊蛋白(C)与选择素结合。所以,人脑中的朊蛋白(C)与选择素的相互作用方式不同于外周组织中的相互作用。这些相互作用的改变可能会产生病理后果。