Linking molecular affinity and cellular specificity in cadherin-mediated adhesion
Linking molecular affinity and cellular specificity in cadherin-mediated adhesion
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DOI：
10.1073/pnas.0905349106
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发表时间：
2009-07-14
影响因子：
11.1
通讯作者：
Honig, Barry H.
中科院分区：
文献类型：
--
作者：
Katsamba, P.;Carroll, K.;Honig, Barry H.
许多细胞-细胞粘附事件是由贴壁细胞表面的钙粘蛋白二聚化介导的。钙粘蛋白介导的过程在体内细胞分选成不同组织中起着核心作用，但旨在模拟这种行为的体外试验产生了不确定的结果。在某些情况下，表达不同钙粘蛋白的细胞表现出同型细胞分选，形成单独的细胞聚集体，而在其他情况下，形成混合的聚集体。第三种模式是观察细胞的混合物表达N-或E-钙粘蛋白，形成不同的同型聚集体，通过异型界面彼此粘附。钙粘蛋白介导的细胞图案化现象的分子基础知之甚少，部分原因是细胞粘附特异性和分子间结合自由能之间的关系尚未建立。为了澄清这个问题，我们测量了N-钙粘蛋白和E-钙粘蛋白的二聚亲和力。这些蛋白质在序列和结构上相似，但能够在多种组织中介导同型细胞模式化行为。发现N-钙粘蛋白形成的同源二聚体具有比E-钙粘蛋白更高的亲和力，并且出乎意料地，N/E-钙粘蛋白异嗜性结合亲和力的强度介于2种同嗜性亲和力之间。我们可以解释观察到的细胞聚集行为，通过使用一个理论框架，建立了分子亲和力和细胞-细胞粘附特异性之间的联系。我们的研究结果说明了不同的嗜同性和嗜异性钙粘蛋白二聚体亲和力之间的差异如何导致同型细胞模式，更一般地说，显示了密切相关的蛋白质如何能够，然而，负责高度特异性的细胞粘附行为。
Many cell-cell adhesive events are mediated by the dimerization of cadherin proteins presented on apposing cell surfaces. Cadherin-mediated processes play a central role in the sorting of cells into separate tissues in vivo, but in vitro assays aimed at mimicking this behavior have yielded inconclusive results. In some cases, cells that express different cadherins exhibit homotypic cell sorting, forming separate cell aggregates, whereas in other cases, intermixed aggregates are formed. A third pattern is observed for mixtures of cells expressing either N- or E-cadherin, which form distinct homotypic aggregates that adhere to one another through a heterotypic interface. The molecular basis of cadherin-mediated cell patterning phenomena is poorly understood, in part because the relationship between cellular adhesive specificity and intermolecular binding free energies has not been established. To clarify this issue, we have measured the dimerization affinities of N-cadherin and E-cadherin. These proteins are similar in sequence and structure, yet are able to mediate homotypic cell patterning behavior in a variety of tissues. N-cadherin is found to form homodimers with higher affinity than does E-cadherin and, unexpectedly, the N/E-cadherin heterophilic binding affinity is intermediate in strength between the 2 homophilic affinities. We can account for observed cell aggregation behaviors by using a theoretical framework that establishes a connection between molecular affinities and cell-cell adhesive specificity. Our results illustrate how graded differences between different homophilic and heterophilic cadherin dimerizaton affinities can result in homotypic cell patterning and, more generally, show how proteins that are closely related can, nevertheless, be responsible for highly specific cellular adhesive behavior.