The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway.
The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway.
复制标题
阿尔茨海默病淀粉样蛋白前体蛋白。
DOI：
10.1016/s0021-9258(19)39590-0
复制
发表时间：
1990
期刊：
影响因子：
--
通讯作者：
L. Fritz
中科院分区：
文献类型：
--
作者：
T. Oltersdorf;P. Ward;T. Henriksson;E. Beattie;R. Neve;I. Lieberburg;L. Fritz
阿尔茨海默病的淀粉样蛋白形成β-肽是作为一个更大的整膜前体蛋白(βAPP)的一部分合成的，已经描述了三个选择性剪接版本的695、751和770个氨基酸。由563个氨基酸组成的第四种贝塔APP形式不包含贝塔多肽区域。最近在HeLa细胞(Weidemann，A.，Konig，G.，Bunke，D.，Fischer，P.，Salbaum，J.M.，Master，C.L.和Beyreuther，K.(1989)Cell 57,115-126)中进行的瞬时表达实验表明，Beta APP经历了几次翻译后修饰，包括切割和分泌其很大一部分胞外区。到目前为止，这种切割后仍然与细胞相关的片段的性质和命运还没有被描述过。这个片段的新陈代谢在阿尔茨海默病中可能具有特殊的意义，因为它必须至少包含部分β-肽。为了研究这个片段的代谢命运，我们建立了过表达695和751氨基酸版本的βAPP的细胞系。脉冲追逐研究表明，该系统与HeLa细胞系统类似，首先合成约98 kDa和108 kDa的膜结合蛋白，携带天冬酰胺连接的糖侧链，然后通过结合硫酸盐、磷酸和包括唾液酸在内的糖基，增加约20 kDa的表观分子质量，加工成更高分子质量的蛋白质。成熟形式的βAPP被切割并迅速分泌，在细胞中留下11.5 kDa的跨膜区和细胞质区域。该片段是稳定的，半衰期至少为4小时。
The amyloid forming beta-peptide of Alzheimer's disease is synthesized as part of a larger integral membrane precursor protein (beta APP) of which three alternatively spliced versions of 695, 751, and 770 amino acids have been described. A fourth beta APP form of 563 amino acids does not contain the beta-peptide region. Recent experiments using transient expression in HeLa cells (Weidemann, A., Konig, G., Bunke, D., Fischer, P., Salbaum, J.M., Masters, C.L., and Beyreuther, K. (1989) Cell 57, 115-126) indicate that the beta APP undergoes several posttranslational modifications including the cleavage and secretion of a large portion of its extracellular domain. The nature and fate of the fragment that remains cell-associated following this cleavage has not heretofore been described. The metabolism of this fragment may have particular significance in Alzheimer's disease since it must contain at least part of the beta-peptide. To study the metabolic fate of this fragment, we have established cell lines overexpressing the 695- and 751-amino acid versions of beta APP. Pulse-chase studies show that this system is similar to the HeLa cell system in that both proteins are synthesized first as membrane-bound proteins of approximately 98 and 108 kDa carrying asparagine-linked sugar side chains and are subsequently processed into higher molecular mass forms by the attachment of sulfate, phosphate, and further sugar groups including sialic acid, adding approximately 20 kDa in apparent molecular mass. The mature form of beta APP is cleaved and rapidly secreted, leaving an 11.5-kDa fragment with the transmembrane region and the cytoplasmic domain behind in the cell. This fragment is stable with a half-life of at least 4 h.