title: Cadherin flexibility provides a key difference between desmosomes and adherens junctions.
abstract: 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.
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Humera
authors: H
authors: Tariq
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Jordi
authors: J
authors: Bella
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Thomas A
authors: TA
authors: Jowitt
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: David F
authors: DF
authors: Holmes
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Mansour
authors: M
authors: Rouhi
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Zhuxiang
authors: Z
authors: Nie
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Clair
authors: C
authors: Baldock
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: David
authors: D
authors: Garrod
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom Lydia.Tabernero@manchester.ac.uk.
authors: Lydia
authors: L
authors: Tabernero
mesh_terms: D022005:Adherens Junctions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D051301:Desmoglein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003896:Desmosomes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2
keywords: adhesion; cadherins; desmosomes; small-angle X-ray scattering; structure