Synaptic neurexin-1 assembles into dynamically regulated active zone nanoclusters
Synaptic neurexin-1 assembles into dynamically regulated active zone nanoclusters
复制标题
DOI：
10.1083/jcb.201812076
复制
发表时间：
2019-08-01
影响因子：
7.8
通讯作者：
Sudhof, Thomas C.
中科院分区：
文献类型：
--
作者：
Trotter, Justin H.;Hao, Junjie;Sudhof, Thomas C.
神经毒素是一种特征明确的突触前细胞粘附分子，可与多种突触后配体结合并组织不同的突触特性。然而，神经毒素的精确突触定位仍然是个谜。使用超分辨率显微镜，我们证明 neurexin-1 在兴奋性突触处形成离散的纳米簇，揭示了突触结构的新颖组织特征。突触通常包含单个纳米簇，该纳米簇包含四个以上的神经毒素-1分子，并且还包括神经毒素-2和/或神经毒素-3亚型。此外，我们发现，neurexin-1 被 ADAM10 生理性切割，与其配体 Neuroligin-1 相似，与 4-6% 的 neurexin-1 相似，与 2-3% 的 Neuroligin-1 相似，存在于成人大脑中作为可溶性胞外域蛋白。阻断 ADAM10 介导的 neurexin-1 裂解可显着增加突触 neurexin-1 含量，从而将包含 neurexin-1 纳米簇的 Homer1(+) 兴奋性突触的百分比从 40-50% 提高到大约 80%，并使每个纳米簇的 neurexin-1 分子数量增加一倍。总而言之，我们的结果揭示了一种意想不到的突触纳米结构域组织，其中 neurexin-1 被组装成离散的突触前纳米簇，这些纳米簇通过胞外域裂解进行动态调节。
Neurexins are well-characterized presynaptic cell adhesion molecules that engage multifarious postsynaptic ligands and organize diverse synapse properties. However, the precise synaptic localization of neurexins remains enigmatic. Using superresolution microscopy, we demonstrate that neurexin-1 forms discrete nanoclusters at excitatory synapses, revealing a novel organizational feature of synaptic architecture. Synapses generally contain a single nanocluster that comprises more than four neurexin-1 molecules and that also includes neurexin-2 and/or neurexin-3 isoforms. Moreover, we find that neurexin-1 is physiologically cleaved by ADAM10 similar to its ligand neuroligin-1, with similar to 4-6% of neurexin-1 and similar to 2-3% of neuroligin-1 present in the adult brain as soluble ectodomain proteins. Blocking ADAM10-mediated neurexin-1 cleavage dramatically increased the synaptic neurexin-1 content, thereby elevating the percentage of Homer1(+) excitatory synapses containing neurexin-1 nanoclusters from 40-50% to similar to 80%, and doubling the number of neurexin-1 molecules per nanocluster. Taken together, our results reveal an unexpected nanodomain organization of synapses in which neurexin-1 is assembled into discrete presynaptic nanoclusters that are dynamically regulated via ectodomain cleavage.