Structural Basis for Plexin Activation and Regulation.
Structural Basis for Plexin Activation and Regulation.
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DOI：
10.1016/j.neuron.2016.06.018
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发表时间：
2016-08-03
期刊：
影响因子：
16.2
通讯作者：
Jones EY
中科院分区：
文献类型：
--
作者：
Kong Y;Janssen BJ;Malinauskas T;Vangoor VR;Coles CH;Kaufmann R;Ni T;Gilbert RJ;Padilla-Parra S;Pasterkamp RJ;Jones EY
A类丛蛋白（PlxnAs）作为信号蛋白受体，控制神经系统发育和可塑性的各个方面，从轴突导向和神经元迁移到突触组织。PlxnA信号需要胞质结构域二聚化，但胞外调控和激活机制仍不清楚。在这里，我们提出的晶体结构的PlxnA（PlxnA 1，PlxnA 2，和PlxnA 4）全胞外域。结构域1-9形成环状构象，C-末端结构域10远离该环状构象指向。我们所有的PlxnA胞外域结构都显示出自抑制性的分子间“头-茎”（结构域1至结构域4-5）相互作用，这通过生物物理测定、活细胞荧光显微镜以及基于细胞的和神经元生长锥塌陷测定来证实。这项工作揭示了PlxnA胞外域的2倍作用：通过分子间头-茎相互作用对胞质结构域施加预信号自抑制分离，并支持基于二聚化的PlxnA活化配体结合。更一般地说，我们的数据确定了一种新的分子机制，防止轴突导向受体的过早激活。结构研究揭示了PlxnA胞外结构域的主要环状构象PlxnA胞外结构域在体外和细胞表面产生头-茎顺式相互作用PlxnA顺式相互作用的破坏诱导细胞和生长锥塌陷PlxnA胞外结构域的结构和相互作用使自身抑制和激活PlxnA信号传导成为可能，这在神经系统发育和可塑性中很重要，需要多层次的调控。Kong等人揭示了PlxnAs的一种新机制，其中通过受体胞外域的不同构象和顺式相互作用实现配体结合前的自抑制和激活后的自抑制。
Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1–9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular “head-to-stalk” (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors. Structural studies reveal a major ring-like conformation for PlxnA ectodomains PlxnA ectodomains make head-to-stalk cis-interactions in vitro and on cell surface Disruption of PlxnA cis-interactions induces cell and growth cone collapse PlxnA ectodomain structure and interaction enable autoinhibition and activation PlxnA signaling, important in nervous system development and plasticity, requires multi-leveled regulation. Kong et al. reveal a novel mechanism for PlxnAs, in which autoinhibition pre- and activation post-ligand binding are achieved through distinct conformations and cis-interactions of the receptor ectodomains.