Identification and characterization of the X-dimer of human P-cadherin: Implications for homophilic cell adhesion

Shota Kudo, Jose M.M. Caaveiro, Shuichiro Goda, Satoru Nagatoishi, Keisuke Ishii, Tadashi Matsuura, Yukio Sudou, Tatsuhiko Kodama, Takao Hamakubo, Kouhei Tsumoto

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11 Citations (Scopus)

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 Ca2+ and governed by specific protein-protein interactions. The attachment of three molecules of Ca2+ with high affinity (Kd = 9 ÎM) stabilizes the monomeric conformation of P-cadherin (Delta;Tm = 17 °C). The Ca2+-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.

Original languageEnglish
Pages (from-to)1742-1752
Number of pages11
JournalBiochemistry
Volume53
Issue number11
DOIs
Publication statusPublished - Mar 25 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry

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    Kudo, S., Caaveiro, J. M. M., Goda, S., Nagatoishi, S., Ishii, K., Matsuura, T., Sudou, Y., Kodama, T., Hamakubo, T., & Tsumoto, K. (2014). Identification and characterization of the X-dimer of human P-cadherin: Implications for homophilic cell adhesion. Biochemistry, 53(11), 1742-1752. https://doi.org/10.1021/bi401341g