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.

在这个项目中，PI将研究细胞间粘附的分子机制。该项目是多尺度和跨学科的，正在制定的战略可以作为其他此类努力的典范，这些努力将现代生物学前沿领域的计算和实验方法相结合。这项研究的一个特别重要的内容是培训在计算和实验工作方面具有专业知识的科学家，包括来自背景非常不同的高级研究人员的联合指导。培训妇女和少数民族科学家是这一研究方案的一个组成部分。一些女性博士后工作在以前的NSF资助的项目已经去了成功的独立研究事业，这一传统将保持。此外，每年夏天，实验室接待少数民族本科生，并接受高中生实习。无论是本科生和研究生的少数民族学生在实验室培训已成为非常成功的研究科学家。该项目的成果将对纳米生物技术行业的劳动力发展和预测工具的发展产生重大影响。该研究项目的目标是阐明钙粘蛋白介导的细胞-细胞粘附的分子机制。钙粘蛋白是细胞表面分子，也具有跨膜区域和与肌动蛋白细胞骨架相互作用的胞质结构域。经典的钙粘蛋白由五个细胞外钙粘蛋白（EC）结构域连接的接头区域。在两个细胞最初相遇时，相对膜表面上的钙粘蛋白彼此结合并引发一系列事件，从形成大的有序组装体开始，最终导致细胞-细胞粘附。该项目包括对经典钙粘蛋白的结构、动力学性质和功能的综合实验和计算研究。现有的三维结构的分析，定点突变体的设计，结合亲和力测量和电子顺磁共振（EPR）光谱将被用来阐明的因素，使钙粘蛋白结合到一个高度特定的方式，尽管彼此相似的序列和结构。EPR还将用于研究细胞间接触和反式（不同细胞）粘附键形成引起的钙粘蛋白柔韧性的变化。粗粒度的分子模拟将被用来了解这些灵活性的变化如何导致形成顺式（相同的细胞）相互作用，驱动细胞表面上的钙粘蛋白的横向聚类。该项目将导致对这类重要分子的更深入理解，并将揭示有关其他粘附分子家族介导细胞-细胞识别的机制的一般原理。该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学以及数学和物理科学理事会物理学部的计算物理学项目共同支持。

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

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

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.

E-cadherin junction formation involves an active kinetic nucleation process

• DOI: 10.1073/pnas.1513775112
• 发表时间: 2015-09-01
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Biswas, Kabir H.;Hartman, Kevin L.;Groves, Jay T.
• 通讯作者: Groves, Jay T.