Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase E
Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase E
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DOI：
10.1016/j.neuron.2004.12.037
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发表时间：
2005-01-20
期刊：
影响因子：
16.2
通讯作者：
Loh, YP
中科院分区：
文献类型：
--
作者：
Lou, H;Kim, SK;Loh, YP
BDNF的活动依赖性分泌在介导突触可塑性中很重要，但它是如何实现的尚不清楚。在这里，我们发现了一个排序基序受体介导的调节分泌BDNF的机制。X-射线晶体结构分析显示，BDNF中存在一个推定的分选基序，1（16）E（18）1（105）D（106），当在酸性残基处突变时，其导致AtT-20细胞中proBDNF向组成型途径的错误分选。一个V20 E突变，以完成一个类似的基序，在神经生长因子重定向的一个显着比例，它从组成的调节途径。建模和结合的研究表明，在BDNF基序的酸性残基与两个基本残基的排序受体，羧肽酶E（CPE）的相互作用。S-35标记实验表明，CPE基因敲除小鼠皮质神经元BDNF的活性依赖性分泌被消除。因此，我们已经确定了一种机制，通过这种机制，特定的基序1（16）E（18）1（105）D（106）与CPIE相互作用，将proBDNF分选到受调节的途径囊泡中，以进行活性依赖性分泌。
Activity-dependent secretion of BDNF is important in mediating synaptic plasticity, but how it is achieved is unclear. Here we uncover a sorting motif receptor-mediated mechanism for regulated secretion of BDNF. X-ray crystal structure analysis revealed a putative sorting Motif, l(16)E(18)l(105)D(106), in BDNF, which when mutated at the acidic residues resulted in missorting of proBDNF to the constitutive pathway in AtT-20 cells. A V20E mutation to complete a similar motif in NGF redirected a significant proportion of it from the constitutive to the regulated pathway. Modeling and binding studies showed interaction of the acidic residues in the BDNF motif with two basic residues in the sorting receptor, carboxypeptidase E (CPE). S-35 labeling experiments demonstrated that activity dependent secretion of BDNF from cortical neurons was obliterated in CPE knockout mice. Thus, we have identified a mechanism whereby a specific Motif l(16)E(18)l(105)D(106) interacts with CPIE to sort proBDNF into regulated pathway vesicles for activity-dependent secretion.