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Visualization of clustered protocadherin neuronal self-recognition complexes

机译：聚集的原钙粘蛋白神经元自我识别复合物的可视化

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摘要

Neurite self-recognition and avoidance are fundamental properties of all nervous systems(1). These processes facilitate dendritic arborization(2,3), prevent formation of autapses(4) and allow free interaction among non-self neurons(1,2,3,4,5). Avoidance among self neurites is mediated by stochastic cell-surface expression of combinations of about 60 isoforms of alpha-, beta- and gamma-clustered protocadherin that provide mammalian neurons with single-cell identities(1,2,4-13). Avoidance is observed between neurons that express identical protocadherin repertoires(2,5), and single-isoform differences are sufficient to prevent self-recognition(10). Protocadherins form isoform-promiscuous cis dimers and isoform-specific homophilic trans dimersi (10,14-20) Although these interactions have previously been characterized in isolation(15,17-20), structures of full-length protocadherin ectodomains have not been determined, and how these two interfaces engage in self-recognition between neuronal surfaces remains unknown. Here we determine the molecular arrangement of full-length clustered protocadherin ectodomains in single-isoform self-recognition complexes, using X-ray crystallography and cryo-electron tomography. We determine the crystal structure of the clustered protocadherin , gamma B4 ectodomain, which reveals a zipper-like lattice that is formed by alternating cis and trans interactions. Using cryo-electron tomography, we show that clustered protocadherin gamma B6 ectodomains tethered to liposomes spontaneously assemble into linear arrays at membrane contact sites, in a configuration that is consistent with the assembly observed in the crystal structure. These linear assemblies pack against each other as parallel arrays to form larger two-dimensional structures between membranes. Our results suggest that the formation of ordered linear assemblies by clustered protocadherins represents the initial self-recognition step in neuronal avoidance, and thus provide support for the isoform-mismatch chain-termination model of protocadherin-mediated self-recognition, which depends on these linear chains(11).
机译：神经突的自我识别和回避是所有神经系统的基本特征（1）。这些过程促进了树突状的树状化（2,3），防止了autapses（4）的形成，并允许非自我神经元之间的自由相互作用（1,2,3,4,5）。自我神经突的回避是通过随机的细胞表面表达介导的约60种α，β和γ簇原钙粘蛋白同工型的组合来实现的，它们为哺乳动物神经元提供了单细胞身份（1,2,4-13）。在表达相同的原钙粘蛋白全集的神经元之间观察到回避（2,5），单一同工型差异足以阻止自我识别（10）。原钙粘蛋白形成同工型混杂顺式二聚体和同工型特异性同型反式二聚体（10,14-20）尽管这些相互作用先前已被隔离（15,17-20）表征，但尚未确定全长原钙粘蛋白胞外域的结构，以及这两个界面如何参与神经元表面之间的自我识别仍然未知。在这里，我们使用X射线晶体学和低温电子断层扫描技术确定单同种型自我识别复合物中全长簇原钙粘蛋白胞外域的分子排列。我们确定簇原钙粘蛋白，γB4胞外域的晶体结构，它揭示了由交替的顺式和反式相互作用形成的拉链状晶格。使用低温电子断层扫描，我们显示束缚在脂质体上的簇状原钙粘蛋白γB6胞外域在膜接触部位自发组装成线性阵列，其结构与在晶体结构中观察到的结构一致。这些线性组件以平行阵列的形式相互排列，以在膜之间形成更大的二维结构。我们的结果表明，由簇状原钙粘着蛋白形成的有序线性组装体代表神经元回避中的初始自我识别步骤，从而为原钙粘着蛋白介导的自我识别的同种型不匹配链终止模型提供了支持，后者取决于这些线性链（11）。

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  • 来源
    《Nature》 |2019年第7755期|280-283|共4页
  • 作者

    Brasch Julia; Goodman Kerry M.; Noble Alex J.; Rapp Micah; Mannepalli Seetha; Bahna Fabiana; Dandey Venkata P.; Bepler Tristan; Berger Bonnie; Maniatis Tom; Potter Clinton S.; Carragher Bridget; Honig Barry; Shapiro Lawrence;

  • 作者单位

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA|Columbia Univ, Dept Syst Biol, New York, NY 10027 USA;

    Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA;

    MIT, Computat & Syst Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Dept Math, Cambridge, MA 02139 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Natl Resource Automated Mol Microscopy, Simons Electron Microscopy Ctr, New York Struct Biol Ctr, New York, NY USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA|Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA|Columbia Univ, Dept Syst Biol, New York, NY 10027 USA|Columbia Univ, Dept Med, New York, NY 10027 USA;

    Columbia Univ, Zuckerman Mind Brain & Behav Inst, New York, NY 10027 USA|Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10027 USA|Columbia Univ, Dept Syst Biol, New York, NY 10027 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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