Role of actin filaments and cis binding in cadherin clustering and patterning.
Role of actin filaments and cis binding in cadherin clustering and patterning.
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肌动蛋白丝和顺式结合在钙粘蛋白聚集和模式化中的作用。
DOI：
10.1371/journal.pcbi.1010257
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发表时间：
2022-07
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
钙粘蛋白形成簇，通过反式和顺式（横向）结合维持细胞间接触。同时，钙粘蛋白和肌动蛋白细胞骨架之间通过钙粘蛋白/F-肌动蛋白连接体之间的相互作用可以通过局部聚集和束缚钙粘蛋白分子来影响钙粘蛋白动力学。尽管有许多实验研究，但对钙粘蛋白和肌动蛋白细胞骨架相互作用如何调节钙粘蛋白聚类的定量、机制理解尚不存在。为了解决这一知识差距，我们开发了钙粘蛋白动力学及其与细胞膜下方肌动蛋白皮层相互作用的粗粒度计算模型。我们的模拟预测表明钙粘蛋白分子之间弱的顺式结合亲和力可以促进大簇的形成。我们还发现肌动蛋白聚集对钙粘蛋白运动的抑制取决于肌动蛋白丝的浓度和长度。这导致钙粘蛋白聚类行为的变化，反映为簇大小和分布以及钙粘蛋白单体轨迹的差异。强钙粘蛋白/肌动蛋白结合可以增强反式和顺式相互作用以及钙粘蛋白聚类。相比之下，由于钙粘蛋白/肌动蛋白结合亲和力较弱，钙粘蛋白-肌动蛋白结合与顺式结合之间对有限钙粘蛋白库的竞争导致临时且不稳定的钙粘蛋白簇。钙粘蛋白分子是跨膜蛋白，其物理连接相邻细胞形成组织。它们通过在每个相邻细胞的质膜中横向聚集在一起并同时与相对细胞上的钙粘蛋白分子结合来实现这一点。这些横向和跨钙粘蛋白相互作用受到相邻细胞质膜下肌动蛋白细胞骨架的动力学和结构的影响。在这项工作中，我们构建了一个基于生物物理学的计算模型来研究钙粘蛋白分子和肌动蛋白丝之间相互作用的性质对钙粘蛋白聚类和细胞间粘附形成的影响。我们的模型表明，当仅模拟钙粘蛋白-钙粘蛋白相互作用时，钙粘蛋白分子之间的弱横向结合导致大钙粘蛋白簇的形成。这一违反直觉的发现调和了一些明显矛盾的先前实验观察结果。当包括钙粘蛋白-肌动蛋白丝相互作用时，该模型预测肌动蛋白网络在不同情况下促进或抑制钙粘蛋白聚类，这取决于肌动蛋白网络和用于钙粘蛋白/肌动蛋白连接的接头蛋白的特性。我们的模型提供了一个重要的概念框架来机械地解释实验观察结果，这些实验观察结果研究细胞-细胞粘附连接处肌动蛋白细胞骨架调节的各种钙粘蛋白聚类行为。
Cadherins build up clusters to maintain intercellular contact through trans and cis (lateral) bindings. Meanwhile, interactions between cadherin and the actin cytoskeleton through cadherin/F-actin linkers can affect cadherin dynamics by corralling and tethering cadherin molecules locally. Despite many experimental studies, a quantitative, mechanistic understanding of how cadherin and actin cytoskeleton interactions regulate cadherin clustering does not exist. To address this gap in knowledge, we developed a coarse-grained computational model of cadherin dynamics and their interaction with the actin cortex underlying the cell membrane. Our simulation predictions suggest that weak cis binding affinity between cadherin molecules can facilitate large cluster formation. We also found that cadherin movement inhibition by actin corralling is dependent on the concentration and length of actin filaments. This results in changes in cadherin clustering behaviors, as reflected by differences in cluster size and distribution as well as cadherin monomer trajectory. Strong cadherin/actin binding can enhance trans and cis interactions as well as cadherin clustering. By contrast, with weak cadherin/actin binding affinity, a competition between cadherin-actin binding and cis binding for a limited cadherin pool leads to temporary and unstable cadherin clusters. Cadherin molecules are transmembrane proteins, which physically link adjacent cells to form tissues. They do so by clustering together laterally in the plasma membrane of each adjoining cell and at the same time associating with cadherin molecules on the opposing cell. These lateral and trans- cadherin interactions are affected by the dynamics and structure of the actin cytoskeleton underlying the plasma membrane of the adjoining cells. In this work, we constructed a biophysics-based computational model to study the effect of the nature of interactions between cadherin molecules and actin filaments on cadherin clustering and cell-cell adhesion formation. Our model suggests that when only cadherin-cadherin interactions are simulated, weak lateral binding between cadherin molecules leads to formation of large cadherin clusters. This counterintuitive finding reconciles a number of apparently contradicting prior experimental observations. When including cadherin-actin filament interactions, the model predicts that the actin network facilitates or inhibits cadherin clustering in different situations that depends on the properties of the actin network and adaptor proteins for cadherin/actin linking. Our model provides an important conceptual framework to mechanistically explain experimental observations that study various cadherin clustering behaviors regulated by the actin cytoskeleton at cell-cell adhesion junctions.
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影响因子：
8.8
作者：
Indra, Indrajyoti;Troyanovsky, Regina B.;Troyanovsky, Sergey M.
通讯作者：
Troyanovsky, Sergey M.
影响因子：
3.4
作者：
Moore, Thomas;Wu, Selwin K.;Neufeld, Zoltan
通讯作者：
Neufeld, Zoltan
DOI：
10.1126/science.1254211
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Buckley CD;Tan J;Anderson KL;Hanein D;Volkmann N;Weis WI;Nelson WJ;Dunn AR
通讯作者：
Dunn AR
影响因子：
5.7
作者：
Harrison, Oliver J.;Jin, Xiangshu;Hong, Soonjin;Bahna, Fabiana;Ahlsen, Goran;Brasch, Julia;Wu, Yinghao;Vendome, Jeremie;Felsovalyi, Klara;Hampton, Cheri M.;Troyanovsky, Regina B.;Ben-Shau, Avinoam;Frank, Joachim;Troyanovsky, Sergey M.;Shapiro, Lawrence;Honig, Barry
通讯作者：
Honig, Barry
影响因子：
21.3
作者：
Bertocchi C;Wang Y;Ravasio A;Hara Y;Wu Y;Sailov T;Baird MA;Davidson MW;Zaidel-Bar R;Toyama Y;Ladoux B;Mege RM;Kanchanawong P
通讯作者：
Kanchanawong P