期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5395-5400
DOI：10.1073/pnas.1420508112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe present here an entirely novel concept in the field of cell-cell adhesion, whereby the flexibility of the extracellular domains of cadherin molecules determines the characteristics and behavior of intercellular junctions. The structure of the ectodomain of the desmosomal cadherin desmoglein 2 shows it is flexible in its calcium-bound form. This flexibility of the desmosomal cadherin ectodomains may be key in facilitating a unique property of desmosomes: the ability to switch from strong calcium-independent hyperadhesion in adult tissues to weaker calcium-dependent adhesion in wounds. Desmosomes and adherens junctions are intercellular adhesive structures essential for the development and integrity of vertebrate tissue, including the epidermis and heart. Their cell adhesion molecules are cadherins: type 1 cadherins in adherens junctions and desmosomal cadherins in desmosomes. A fundamental difference is that desmosomes have a highly ordered structure in their extracellular region and exhibit calcium-independent hyperadhesion, whereas adherens junctions appear to lack such ordered arrays, and their adhesion is always calcium-dependent. We present here the structure of the entire ectodomain of desmosomal cadherin desmoglein 2 (Dsg2), using a combination of small-angle X-ray scattering, electron microscopy, and solution-based biophysical techniques. This structure reveals that the ectodomain of Dsg2 is flexible even in the calcium-bound state and, on average, is shorter than the type 1 cadherin crystal structures. The Dsg2 structure has an excellent fit with the electron tomography reconstructions of human desmosomes. This fit suggests an arrangement in which desmosomal cadherins form trans interactions but are too far apart to interact in cis, in agreement with previously reported observations. Cadherin flexibility may be key to explaining the plasticity of desmosomes that maintain tissue integrity in their hyperadhesive form, but can adopt a weaker, calcium-dependent adhesion during wound healing and early development.
