title: Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4.
abstract: Protocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhγB3, a member of the γ subfamily of clustered Pcdhs. Structure and sequence comparisons of α, β, and γ clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.|Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Nicoludis
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
authors.forename: Bennett E
authors.initials: BE
authors.lastname: Vogt
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, United States.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Green
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, United States.|Applied Bioinformatics, Department of Computer Science, University of Tübingen, Tübingen, Germany.
authors.forename: Charlotta Pi
authors.initials: CP
authors.lastname: Schärfe
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, United States.
authors.forename: Debora S
authors.initials: DS
authors.lastname: Marks
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
authors.forename: Rachelle
authors.identifier: 0000-0002-9177-054X
authors.initials: R
authors.lastname: Gaudet
mesh_terms: D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D000091363:Protocadherins
chemical_list: D015820:Cadherins; C000624548:PCDHGB3 protein, human; D000091363:Protocadherins
keywords: biophysics; cell adhesion; computational biology; crystallography; human; protocadherins; sequence coevolution; structural biology; systems biology