Molecular Mechanisms in Adhesion Protein Mediated Neuron-Neuron Recognition

粘附蛋白介导的神经元-神经元识别的分子机制

• 批准号: 1914542
• 负责人: Barry Honig
• 金额: $ 100万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1914542&HistoricalAwards=false
• 关键词: Molecular; Mechanisms; Adhesion; Protein; Mediated

How neurons interact with one another to create the complex wiring diagram of a mature vertebrate brain is a major mystery. One of the many problems that arises is how neurons are "barcoded"; that is, how they distinguish self from non-self. This ability is essential since, without it, there would be nothing to prevent neurons from forming connections (synapses) with themselves, essentially creating a short circuit within the brain. The fundamental goal of this project is to understand how neurons are barcoded. Neuron-neuron recognition is mediated by protein-protein interactions. This project focuses on members of the Clustered Protocadherins (Pcdh) protein family that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". The research will involve computer simulations, biophysical measurements, and high-resolution microscopy experiments to experimentally validate and describe the barcoding mechanism in cells. A particularly important element of the research is the development of scientists with expertise in both computational and experimental work. The training of women and minority scientists is an integral component of the proposed research program. Both undergraduate and graduate minority students trained to be on a trajectory to become highly successful research scientists. The main objective of the project is to advance understanding of the molecular basis of neuron-neuron recognition. Cell-cell interactions are mediated by protein-protein interactions and the long-range goal of the research is to understand the underlying mechanisms. Specifically, how do protein-protein interactions involving cell surface proteins mediate highly specific cell-cell interactions. Given the complexity of the nervous system, neuron-neuron interactions offer a unique challenge in this regard. The research focuses on the clustered Protocadherins (Pcdhs) that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". These are neuronal barcoding proteins. The research involves computational studies to determine how homophilic specificity is coded on Pcdh-Pcdh interfaces, the design of mutants to test the hypotheses that are generated, and their testing experimentally. A second focus of the research is to elucidate the molecular basis of neuronal barcoding. A novel chain termination mechanism based on the assembly of crystalline-like "molecular zippers" in cell-cell interfaces has been proposed and is consistent with all available experimental data. The model will now be explored with multi-scale simulations, and in vitro and in vivo experimental studies. Notably, the model introduces new concepts in the molecular basis of cell-cell recognition. This project is supported by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

神经元是如何相互作用来创建成熟脊椎动物大脑的复杂接线图的，这是一个主要的谜团。随之而来的诸多问题之一就是神经元是如何“条形码”的；也就是说，它们如何区分自我和非我。这种能力是必不可少的，因为如果没有这种能力，就没有什么可以阻止神经元与自己形成连接(突触)，本质上是在大脑中造成短路。这个项目的基本目标是了解神经元是如何进行条形码编码的。神经元-神经元识别是由蛋白质-蛋白质相互作用介导的。这个项目的重点是聚集型原钙粘附素(Pcdh)蛋白家族的成员，这些蛋白家族为单个脊椎动物神经元建立了独特的身份，使它们能够区分“自我”和“非自我”。这项研究将包括计算机模拟、生物物理测量和高分辨率显微镜实验，以实验验证和描述细胞中的条形码机制。这项研究的一个特别重要的因素是培养在计算和实验工作方面都有专长的科学家。对女性和少数民族科学家的培训是拟议的研究方案的一个组成部分。无论是本科生还是少数民族研究生，都被培养成一名非常成功的研究科学家。该项目的主要目标是促进对神经元-神经元识别的分子基础的了解。细胞与细胞的相互作用是由蛋白质与蛋白质的相互作用所介导的，这项研究的长期目标是了解其潜在的机制。具体地说，涉及细胞表面蛋白的蛋白质-蛋白质相互作用如何调节高度特异性的细胞-细胞相互作用。鉴于神经系统的复杂性，神经元之间的相互作用在这方面提出了独特的挑战。这项研究的重点是聚集型原钙粘附素(Pcdhs)，它为单个脊椎动物神经元建立了独特的身份，使它们能够区分“自我”和“非自我”。这些是神经元条码蛋白。这项研究涉及计算研究，以确定同型特异性是如何在Pcdh-Pcdh界面上编码的，设计突变体来测试产生的假设，以及它们的实验测试。这项研究的第二个重点是阐明神经元条码的分子基础。提出了一种新的基于晶状分子拉链在细胞-细胞界面组装的链终止机制，并与现有的实验数据相一致。现在将通过多尺度模拟以及体外和体内实验研究来探索该模型。值得注意的是，该模型在细胞-细胞识别的分子基础上引入了新的概念。该项目由生物科学局分子和细胞生物科学部的分子生物物理组支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为是值得支持的。

项目成果

Sensing Actin Dynamics through Adherens Junctions

• DOI: 10.1016/j.celrep.2020.01.106
• 发表时间: 2020-02-25
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Indra, Indrajyoti;Troyanovsky, Regina B.;Troyanovsky, Sergey M.
• 通讯作者: Troyanovsky, Sergey M.

DIP/Dpr interactions and the evolutionary design of specificity in protein families

• DOI: 10.1038/s41467-020-15981-8
• 发表时间: 2020-05-01
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sergeeva, Alina P.;Katsamba, Phinikoula S.;Honig, Barry
• 通讯作者: Honig, Barry

Visualization of clustered protocadherin neuronal self-recognition complexes

• DOI: 10.1038/s41586-019-1089-3
• 发表时间: 2019-05-09
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Brasch, Julia;Goodman, Kerry M.;Shapiro, Lawrence
• 通讯作者: Shapiro, Lawrence

Sorting of cadherin–catenin-associated proteins into individual clusters

将钙粘蛋白-连环蛋白相关蛋白分类到各个簇中

• DOI: 10.1073/pnas.2105550118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Troyanovsky, Regina B.;Sergeeva, Alina P.;Indra, Indrajyoti;Chen, Chi-Shuo;Kato, Rei;Shapiro, Lawrence;Honig, Barry;Troyanovsky, Sergey M.
• 通讯作者: Troyanovsky, Sergey M.

Push-pull mechanics of E-cadherin ectodomains in biomimetic adhesions

E-钙粘蛋白胞外域在仿生粘连中的推拉力学

• DOI: 10.1016/j.bpj.2023.07.026
• 发表时间: 2023
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Nagendra, Kartikeya;Izzet, Adrien;Judd, Nicolas B.;Zakine, Ruben;Friedman, Leah;Harrison, Oliver J.;Pontani, Léa-Laetitia;Shapiro, Lawrence;Honig, Barry;Brujic, Jasna
• 通讯作者: Brujic, Jasna