title: Identification and characterization of the X-dimer of human P-cadherin: implications for homophilic cell adhesion.
abstract: Cell adhesion mediated by cadherins depends critically on the homophilic trans-dimerization of cadherin monomers from apposing cells, generating the so-called strand-swap dimer (ss-dimer). Recent evidence indicates that the ss-dimer is preceded by an intermediate species known as the X-dimer. Until now, the stabilized form of the X-dimer had only been observed in E-cadherin among the classical type I cadherins. Herein, we report the isolation and characterization of the analogous X-dimer of human P-cadherin. Small-angle X-ray scattering (SAXS) and site-directed mutagenesis data indicates that the overall architecture of the X-dimer of human P-cadherin is similar to that of E-cadherin. The X-dimerization is triggered by Ca(2+) and governed by specific protein-protein interactions. The attachment of three molecules of Ca(2+) with high affinity (Kd = 9 μM) stabilizes the monomeric conformation of P-cadherin (ΔTm = 17 °C). The Ca(2+)-stabilized monomer subsequently dimerizes in the X-configuration by establishing protein-protein interactions that require the first two extracellular domains of the cadherin. The homophilic X-dimerization is very specific, as the presence of the highly homologous E-cadherin does not interfere with the self-recognition of P-cadherin. These data suggest that the X-dimer could play a key role in the specific cell-cell adhesion mediated by human P-cadherin.
authors.affiliation: Department of Chemistry & Biotechnology, The University of Tokyo , Tokyo 108-8639, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Kudo
authors.forename: Jose M M
authors.initials: JM
authors.lastname: Caaveiro
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Goda
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagatoishi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishii
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sudou
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
mesh_terms: D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology*; D053838:Scattering, Small Angle; D013816:Thermodynamics; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D015820:Cadherins