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首页> 外文期刊>Journal of Molecular Biology >Structural Plasticity of Neurexin 1α: Implications for its Role as Synaptic Organizer
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Structural Plasticity of Neurexin 1α: Implications for its Role as Synaptic Organizer

机译：Neurexin1α的结构可塑性：对其作为突触组织者的作用的影响

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α-Neurexins are synaptic organizing molecules implicated in neuropsychiatric disorders. They bind and arrange an array of different partners in the synaptic cleft. The extracellular region of neurexin 1α (n1α) contains six LNS domains (L1–L6) interspersed by three Egf-like repeats. N1α must encode highly evolved structure–function relationships in order to fit into the narrow confines of the synaptic cleft, and also recruit its large, membrane-bound partners. Internal molecular flexibility could provide a solution; however, it is challenging to delineate because currently no structural methods permit high-resolution structure determination of large, flexible, multi-domain protein molecules. To investigate the structural plasticity of n1α, in particular the conformation of domains that carry validated binding sites for different protein partners, we used a panel of structural techniques. Individual particle electron tomography revealed that the N-terminally and C-terminally tethered domains, L1 and L6, have a surprisingly limited range of conformational freedom with respect to the linear central core containing L2 through L5. A 2.8-? crystal structure revealed an unexpected arrangement of the L2 and L3 domains. Small-angle X-ray scattering and electron tomography indicated that incorporation of the alternative splice insert SS6 relieves the restricted conformational freedom between L5 and L6, suggesting that SS6 may work as a molecular toggle. The architecture of n1α thus encodes a combination of rigid and flexibly tethered domains that are uniquely poised to work together to promote its organizing function in the synaptic cleft, and may permit allosterically regulated and/or concerted protein partner binding.
机译：α-奈氏蛋白是涉及神经精神疾病的突触组织分子。它们在突触裂缝中绑定并安排一系列不同的合作伙伴。 Neurexin1α（N1α）的细胞外区域含有六个LNS结构域（L1-L6），其三种EGF样重复。 N1α必须编码高度发展的结构功能关系，以适应突触裂缝的狭窄范围，并且还招募其大型膜结合的合作伙伴。内部分子柔韧性可以提供溶液;然而，划界是挑战，因为目前没有结构方法允许大，柔性，多域蛋白质分子的高分辨率结构测定。为了研究N1α的结构可塑性，特别是携带不同蛋白质合作伙伴的验证结合位点的结构域的构象，我们使用了结构技术。单个粒子电子断层扫描显示，N-末端和C末端旋转域，L1和L6，相对于含有L2至L5的线性中心核心的一致性自由度。 2.8-？晶体结构揭示了L2和L3结构域的意外布置。小角度X射线散射和电子断层扫描表明，替代的拼接插入件SS6的掺入可缓解L5和L6之间的受限构象自由度，表明SS6可以作为分子切炸。因此，N1α的结构编码了刚性和柔性的束缚结构域的组合，其独特地倾向于共同努力，以促进其在突触裂缝中的组织功能，并且可以允许构图调节和/或协调的蛋白质合作伙伴结合。

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