Structural basis of adhesive binding by desmocollins and desmogleins.
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.
Department of Systems Biology, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
Oliver J
OJ
Harrison
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032;
Julia
J
Brasch
Department of Systems Biology, Columbia University, New York, NY 10032; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032;
Gorka
G
Lasso
Department of Systems Biology, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
Phinikoula S
PS
Katsamba
Department of Systems Biology, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
Goran
G
Ahlsen
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.
Barry
B
Honig
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.
Lawrence
L
Shapiro
D000269:Adhesives / Q000737:chemistry* / Q000378:metabolism; D051187:Desmocollins / Q000737:chemistry* / Q000378:metabolism; D051182:Desmogleins / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D011487:Protein Conformation
D000269:Adhesives; D051187:Desmocollins; D051182:Desmogleins
cadherin; cell adhesion; desmosome; heterophilic binding