TY - JOUR
T1 - Adhesive Dimerization of Human P-Cadherin Catalyzed by a Chaperone-like Mechanism
AU - Kudo, Shota
AU - Caaveiro, Jose M.M.
AU - Tsumoto, Kouhei
N1 - Funding Information:
This work was supported by the Funding program for world-leading Innovative R&D on Science and Technology (FIRST) from JSPS , the Platform for Drug Discovery, Informatics, and Structural Life Science (MEXT ), JSPS Grants-in-Aid for Scientific Research 25249115 (K.T.) and 15K06962 (J.M.M.C.), and a Grant-in-Aid for JSPS fellows (S.K.). We thank the staff of the Photon Factory (Tsukuba, Japan) for excellent technical support. Access to beamlines BL5A, AR-NW12A, and AR-NE3A was granted by the Photon Factory Advisory Committee (Proposal Numbers 2011G574, 2012G191, and 2013G738). We thank Dr. Mochida for expert advice with the AUC experiments, and Dr. Iwanari and Mr. Arai for their assistance during the preparation of cells expressing recombinant human P-cadherin.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2016.07.002
DO - 10.1016/j.str.2016.07.002
M3 - Article
C2 - 27545624
AN - SCOPUS:84985947193
SN - 0969-2126
VL - 24
SP - 1523
EP - 1536
JO - Structure
JF - Structure
IS - 9
ER -
