A peptide zipcode sufficient for anterograde transport within amyloid precursor protein.
A peptide zipcode sufficient for anterograde transport within amyloid precursor protein.
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足以在淀粉样前体蛋白内顺行运输的肽邮政编码。
DOI：
10.1073/pnas.0607527103
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发表时间：
2006
影响因子：
11.1
通讯作者：
Bearer,ElaineL
中科院分区：
文献类型：
--
作者：
Satpute-Krishnan,Prasanna;DeGiorgis,JosephA;Conley,MichaelP;Jang,Marcus;Bearer,ElaineL
膜结合细胞器的快速顺行运输将神经元细胞体中合成的分子向外递送到远处的突触。鉴定细胞器上的分子“邮政编码”，介导这种定向运输的微管马达的附着和激活是一个主要的调查领域。在这里，我们确定了一个短的肽序列（15个氨基酸）从淀粉样前体蛋白（APP-C）的胞质C末端足以介导肽缀合珠在鱿鱼巨轴突的顺行运输。APP-C珠以快速轴突运输速率（0.53 μm/s的平均速度，0.9 μm/s的最大速度）行进，而与共注射到相同轴突中的其他肽偶联的珠在注射部位保持静止。这种运输似乎是生理性的，因为它模拟了内源性鱿鱼细胞器和与C99缀合的珠子的行为，C99是一种含有淀粉样前体蛋白（APP）全长胞质结构域的多肽。与缺乏APP-C结构域的APP缀合的珠不被转运。共注射APP-C肽使C99珠运动性降低75%，并消除APP-C珠运动性，表明可溶性肽与蛋白质缀合的珠竞争轴浆马达。APP-C结构域从鱿鱼到人是保守的（13/15 aa），并且来自鱿鱼或人APP的肽的行为相似。因此，我们已经确定了一个保守的肽邮政编码足以直接顺行运输外源性货物，并建议APP的作用之一可能是招募和激活轴突机械内源性货物运输。
Fast anterograde transport of membrane-bound organelles delivers molecules synthesized in the neuronal cell body outward to distant synapses. Identification of the molecular “zipcodes” on organelles that mediate attachment and activation of microtubule-based motors for this directed transport is a major area of inquiry. Here we identify a short peptide sequence (15 aa) from the cytoplasmic C terminus of amyloid precursor protein (APP-C) sufficient to mediate the anterograde transport of peptide-conjugated beads in the squid giant axon. APP-C beads travel at fast axonal transport rates (0.53 μm/s average velocity, 0.9 μm/s maximal velocity) whereas beads coupled to other peptides coinjected into the same axon remain stationary at the injection site. This transport appears physiologic, because it mimics behavior of endogenous squid organelles and of beads conjugated to C99, a polypeptide containing the full-length cytoplasmic domain of amyloid precursor protein (APP). Beads conjugated to APP lacking the APP-C domain are not transported. Coinjection of APP-C peptide reduces C99 bead motility by 75% and abolishes APP-C bead motility, suggesting that the soluble peptide competes with protein-conjugated beads for axoplasmic motor(s). The APP-C domain is conserved (13/15 aa) from squid to human, and peptides from either squid or human APP behave similarly. Thus, we have identified a conserved peptide zipcode sufficient to direct anterograde transport of exogenous cargo and suggest that one of APP's roles may be to recruit and activate axonal machinery for endogenous cargo transport.