title: Adhesive Dimerization of Human P-Cadherin Catalyzed by a Chaperone-like Mechanism.
abstract: Orderly assembly of classical cadherins governs cell adhesion and tissue maintenance. A key event is the strand-swap dimerization of the extracellular ectodomains of two cadherin molecules from apposing cells. Here we have determined crystal structures of P-cadherin in six different conformational states to elaborate a motion picture of its adhesive dimerization at the atomic level. The snapshots revealed that cell-adhesive dimerization is facilitated by several intermediate states collectively termed X-dimer in analogy to other classical cadherins. Based on previous studies and on the combined structural, kinetic, thermodynamic, biochemical, and cellular data reported herein, we propose that the adhesive dimerization of human P-cadherin is achieved by a stepwise mechanism analogous to that of assembly chaperones. This mechanism, applicable to type I classical cadherins, confers high specificity and fast association rates. We expect these findings to guide innovative therapeutic approaches targeting P-cadherin in cancer.
authors.affiliation: Department of Chemistry & Biotechnology, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Kudo
authors.affiliation: Department of Bioengineering, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: jose@bioeng.t.u-tokyo.ac.jp.
authors.forename: Jose M M
authors.initials: JM
authors.lastname: Caaveiro
authors.affiliation: Department of Chemistry & Biotechnology, The University of Tokyo, Tokyo 108-8639, Japan; Department of Bioengineering, The University of Tokyo, Tokyo 108-8639, Japan; Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: tsumoto@bioeng.t.u-tokyo.ac.jp.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD; D001665:Binding Sites; D055162:Biocatalysis; D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018832:Molecular Chaperones; D011994:Recombinant Proteins