The Molecular Basis of Cadherin-Mediated Cell Adhesion

钙粘蛋白介导的细胞粘附的分子基础

• 批准号: 1412472
• 负责人: Barry Honig
• 金额: $ 103.65万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1412472&HistoricalAwards=false
• 关键词: Molecular; Basis; Cadherin; Mediated; Cell

In this project the PI will study the molecular mechanisms that underlie cell-cell adhesion. The project is multi-scale and interdisciplinary in nature and the strategy that is being developed can serve as a model for other such efforts that integrate computational and experimental methods in cutting edge areas of modern biology. A particularly important element of this research is the training of scientists with expertise in both computational and experimental work including joint mentoring from senior researchers with very different backgrounds. The training of women and minority scientists is an integral component of this research program. A number of women postdocs working on previous NSF funded projects have gone on to successful independent research careers and this tradition will be maintained. In addition, each summer the lab hosts minority undergraduate students and accepts high school students as interns. Both undergraduate and graduate minority students trained in the lab have become highly successful research scientists. The outcomes of this project will have substantial impacts on the workforce development and on the development of predictive tools in nanobiotechnology industry.The objective of this research project is to elucidate the molecular mechanisms that underlie cadherin-mediated cell-cell adhesion. Cadherins are cell surface molecules that also have a trans-membrane region and a cytoplasmic domain that interacts with the actin cytoskeleton. Classical cadherins consist of five extracellular cadherin (EC) domains connected by linker regions. Upon initial encounter of two cells, cadherins on opposing membrane surfaces bind to one another and initiate a series of events, beginning with the formation of large ordered assemblies, that ultimately lead to cell-cell adhesion. The project involves integrated experimental and computational studies on the structure, dynamical properties and function of classical cadherins. Analysis of existing three-dimensional structures, the design of site directed mutants, binding affinity measurements and Electron Paramagnetic Resonance (EPR) spectroscopy will be used to elucidate the factors that enable cadherins to bind to one another in a highly specific fashion, despite being similar to one another in sequence and structure. EPR will also be used to study changes in cadherin flexibility resulting from cell-cell contact and the formation of trans (different cell) adhesive bonds. Coarse-grained molecular simulations will be used to understand how these changes in flexibility lead to the formation of cis (same cell) interactions that drive the lateral clustering of cadherins on cell surfaces. The project will lead to a deeper understanding of this important class of molecules and will also reveal general principles regarding the mechanisms employed by other families of adhesion molecules to mediate cell-cell recognition. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.

在该项目中，PI将研究基于细胞细胞粘附的分子机制。该项目本质上是多尺度和跨学科的，而正在制定的策略可以作为将计算和实验方法整合到现代生物学尖端领域的其他努力的模型。这项研究的一个特别重要的要素是对具有专业知识的科学家在计算和实验性工作中的培训，包括来自具有截然背景的高级研究人员的共同指导。妇女和少数民族科学家的培训是该研究计划的组成部分。许多从事先前NSF资助项目的妇女博士后已经从事成功的独立研究职业，这将维持这一传统。此外，每年夏天，实验室都有少数族裔本科生，并接受高中生作为实习生。在实验室培训的本科生和少数族裔学生都已经成为非常成功的研究科学家。该项目的结果将对劳动力发展和纳米生物技术行业的预测工具的开发产生重大影响。该研究项目的目的是阐明基于钙粘蛋白介导的细胞细胞粘附的分子机制。钙粘蛋白是具有跨膜区域的细胞表面分子和与肌动蛋白细胞骨架相互作用的细胞质结构域。经典的钙粘着蛋白由连接区域连接的五个细胞外钙粘蛋白（EC）结构域组成。在两个细胞的初始相遇后，相对膜表面上的钙粘着蛋白相互结合并引发一系列事件，从形成大量有序的组件开始，最终导致细胞细胞粘附。该项目涉及有关经典钙粘蛋白的结构，动力学特性和功能的集成实验和计算研究。分析现有的三维结构，位置的定向突变体的设计，结合亲和力测量和电子顺磁共振（EPR）光谱法将用于阐明使钙粘蛋白能够以高度特定方式彼此结合的因素，尽管序列和结构在序列和结构上相似。 EPR还将用于研究由细胞 - 细胞接触和反式（不同细胞）粘合键的形成引起的钙粘蛋白柔性的变化。粗粒分子模拟将用于了解柔韧性的这些变化如何导致CIS（相同细胞）相互作用的形成，从而驱动钙粘着蛋白在细胞表面上的横向聚类。该项目将使人们对这一重要类别的分子有更深入的了解，还将揭示有关其他粘附分子家族在介导细胞细胞识别的机制的一般原则。该项目由分子生物物理学在生物学科学局和分子生物科学的分裂中共同支持，在数学和物理科学局的物理学划分中，该项目在生物科学局和计算物理计划中共同支持。

项目成果

Structural basis of adhesive binding by desmocollins and desmogleins

• DOI: 10.1073/pnas.1606272113
• 发表时间: 2016-06-28
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Harrison, Oliver J.;Brasch, Julia;Shapiro, Lawrence
• 通讯作者: Shapiro, Lawrence

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

Spatial and temporal organization of cadherin in punctate adherens junctions

• DOI: 10.1073/pnas.1720826115
• 发表时间: 2018-05-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Indra, Indrajyoti;Choi, Jongho;Troyanovsky, Sergey M.
• 通讯作者: Troyanovsky, Sergey M.

Molecular basis of sidekick-mediated cell-cell adhesion and specificity

• DOI: 10.7554/elife.19058
• 发表时间: 2016-09-19
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Goodman, Kerry M.;Yamagata, Masahito;Shapiro, Lawrence
• 通讯作者: Shapiro, Lawrence

Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins

• DOI: 10.1073/pnas.1708319114
• 发表时间: 2017-10-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Larsen, Ida Signe Bohse;Narimatsu, Yoshiki;Halim, Adnan
• 通讯作者: Halim, Adnan