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Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7160-5. doi: 10.1073/pnas.1606272113. Epub 2016 Jun 13.

Structural basis of adhesive binding by desmocollins and desmogleins.

Author information

1
Department of Systems Biology, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
2
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032;
3
Department of Systems Biology, Columbia University, New York, NY 10032; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032;
4
Department of Systems Biology, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032; Department of Medicine, Columbia University, New York, NY 10032; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032 bh6@cumc.columbia.edu shapiro@convex.hhmi.columbia.edu.
5
Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032 bh6@cumc.columbia.edu shapiro@convex.hhmi.columbia.edu.

Abstract

Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.

KEYWORDS:

cadherin; cell adhesion; desmosome; heterophilic binding

PMID:
27298358
PMCID:
PMC4932976
DOI:
10.1073/pnas.1606272113
[Indexed for MEDLINE]
Free PMC Article

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