Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online April 18, 2002
Science DOI: 10.1126/science.1071559

Reports

Submitted on March 6, 2002
Accepted on April 9, 2002

Structure of the C-Cadherin Ectodomain and Implications for the Mechanism of Cell Adhesion

Titus J. Boggon 1, John Murray 1, Sophie Chappuis-Flament 2, Ellen Wong 2, Barry M. Gumbiner 2, Lawrence Shapiro 3*

1 Departments of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA; Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029, USA.
2 Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
3 Departments of Biochemistry and Molecular Biophysics, Department of Ophthalmology, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA; Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029, USA.

* To whom correspondence should be addressed. E-mail: Shapiro{at}convex.hhmi.columbia.edu.

Cadherins are transmembrane proteins that mediate adhesion between cells in the solid tissues of animals. Here we present the 3.1Å resolution crystal structure of the whole, functional extracellular domain from C-cadherin, a representative "classical" cadherin. The structure suggests a molecular mechanism for adhesion between cells by classical cadherins, and provides a new framework for understanding both cis (same cell) and trans (juxtaposed cell) cadherin interactions. The trans adhesive interface is a two-fold symmetric interaction defined by a conserved tryptophan side chain at the membrane-distal end of a cadherin molecule from one cell, which inserts into a hydrophobic pocket at the membrane-distal end of a cadherin molecule from the opposing cell.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Regulation of Homotypic Cell-Cell Adhesion by Branched N-Glycosylation of N-cadherin Extracellular EC2 and EC3 Domains.
H.-B. Guo, H. Johnson, M. Randolph, and M. Pierce (2009)
J. Biol. Chem. 284, 34986-34997
   Abstract »    Full Text »    PDF »
The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters.
E. Klaile, O. Vorontsova, K. Sigmundsson, M. M. Muller, B. B. Singer, L.-G. Ofverstedt, S. Svensson, U. Skoglund, and B. Obrink (2009)
J. Cell Biol. 187, 553-567
   Abstract »    Full Text »    PDF »
Structure and Biochemistry of Cadherins and Catenins.
L. Shapiro and W. I. Weis (2009)
Cold Spring Harb Perspect Biol 1, a003053
   Abstract »    Full Text »    PDF »
The Mechanotransduction Machinery of Hair Cells.
N. Grillet, P. Kazmierczak, W. Xiong, M. Schwander, A. Reynolds, H. Sakaguchi, J. Tokita, B. Kachar, and U. Muller (2009)
Science Signaling 2, pt5
   Abstract »    Full Text »    PDF »
Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3.
R. Arulanandam, A. Vultur, J. Cao, E. Carefoot, B. E. Elliott, P. F. Truesdell, L. Larue, H. Feracci, and L. Raptis (2009)
Mol. Cancer Res. 7, 1310-1327
   Abstract »    Full Text »    PDF »
Linking molecular affinity and cellular specificity in cadherin-mediated adhesion.
P. Katsamba, K. Carroll, G. Ahlsen, F. Bahna, J. Vendome, S. Posy, M. Rajebhosale, S. Price, T. M. Jessell, A. Ben-Shaul, et al. (2009)
PNAS 106, 11594-11599
   Abstract »    Full Text »    PDF »
Endothelial barrier stabilization by a cyclic tandem peptide targeting VE-cadherin transinteraction in vitro and in vivo.
W.-M. Heupel, A. Efthymiadis, N. Schlegel, T. Muller, Y. Baumer, W. Baumgartner, D. Drenckhahn, and J. Waschke (2009)
J. Cell Sci. 122, 1616-1625
   Abstract »    Full Text »    PDF »
Resolving cadherin interactions and binding cooperativity at the single-molecule level.
Y. Zhang, S. Sivasankar, W. J. Nelson, and S. Chu (2009)
PNAS 106, 109-114
   Abstract »    Full Text »    PDF »
Biophysical Properties of Cadherin Bonds Do Not Predict Cell Sorting.
Q. Shi, Y.-H. Chien, and D. Leckband (2008)
J. Biol. Chem. 283, 28454-28463
   Abstract »    Full Text »    PDF »
Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain.
S. A. Dames, E. Bang, D. Haussinger, T. Ahrens, J. Engel, and S. Grzesiek (2008)
J. Biol. Chem. 283, 23485-23495
   Abstract »    Full Text »    PDF »
Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction.
W.-M. Heupel, D. Zillikens, D. Drenckhahn, and J. Waschke (2008)
J. Immunol. 181, 1825-1834
   Abstract »    Full Text »    PDF »
Establishment of cell-cell junctions depends on the oligomeric states of VE-cadherin.
S. Bibert, H. Ayari, D. Riveline, E. Concord, B. Hermant, T. Vernet, and D. Gulino-Debrac (2008)
J. Biochem. 143, 821-832
   Abstract »    Full Text »    PDF »
Fibrogenic fibroblasts increase intercellular adhesion strength by reinforcing individual OB-cadherin bonds.
P. Pittet, K. Lee, A. J. Kulik, J.-J. Meister, and B. Hinz (2008)
J. Cell Sci. 121, 877-886
   Abstract »    Full Text »    PDF »
P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle.
Y. Shimomura, M. Wajid, L. Shapiro, and A. M. Christiano (2008)
Development 135, 743-753
   Abstract »    Full Text »    PDF »
VE-Cadherin: The Major Endothelial Adhesion Molecule Controlling Cellular Junctions and Blood Vessel Formation.
D. Vestweber (2008)
Arterioscler Thromb Vasc Biol 28, 223-232
   Abstract »    Full Text »    PDF »
Two Stage Cadherin Kinetics Require Multiple Extracellular Domains but Not the Cytoplasmic Region.
Y.-H. Chien, N. Jiang, F. Li, F. Zhang, C. Zhu, and D. Leckband (2008)
J. Biol. Chem. 283, 1848-1856
   Abstract »    Full Text »    PDF »
Structural Elements Necessary for Oligomerization, Trafficking, and Cell Sorting Function of Paraxial Protocadherin.
X. Chen, C. Molino, L. Liu, and B. M. Gumbiner (2007)
J. Biol. Chem. 282, 32128-32137
   Abstract »    Full Text »    PDF »
Stable and Unstable Cadherin Dimers: Mechanisms of Formation and Roles in Cell Adhesion.
R. B. Troyanovsky, O. Laur, and S. M. Troyanovsky (2007)
Mol. Biol. Cell 18, 4343-4352
   Abstract »    Full Text »    PDF »
Structural plasticity in Ig superfamily domain 4 of ICAM-1 mediates cell surface dimerization.
X. Chen, T. D. Kim, C. V. Carman, L.-Z. Mi, G. Song, and T. A. Springer (2007)
PNAS 104, 15358-15363
   Abstract »    Full Text »    PDF »
Structure of a Tyrosine Phosphatase Adhesive Interaction Reveals a Spacer-Clamp Mechanism.
A. R. Aricescu, C. Siebold, K. Choudhuri, V. T. Chang, W. Lu, S. J. Davis, P. A. van der Merwe, and E. Y. Jones (2007)
Science 317, 1217-1220
   Abstract »    Full Text »    PDF »
Thermodynamically reengineering the listerial invasion complex InlA/E-cadherin.
T. Wollert, D. W. Heinz, and W.-D. Schubert (2007)
PNAS 104, 13960-13965
   Abstract »    Full Text »    PDF »
Single-Molecule Experiments in Vitro and in Silico.
M. Sotomayor and K. Schulten (2007)
Science 316, 1144-1148
   Abstract »    Full Text »    PDF »
Cadherin Conformations Associated with Dimerization and Adhesion.
H. Tsuiji, L. Xu, K. Schwartz, and B. M. Gumbiner (2007)
J. Biol. Chem. 282, 12871-12882
   Abstract »    Full Text »    PDF »
Depletion of E-Cadherin Disrupts Establishment but Not Maintenance of Cell Junctions in Madin-Darby Canine Kidney Epithelial Cells.
C. T. Capaldo and I. G. Macara (2007)
Mol. Biol. Cell 18, 189-200
   Abstract »    Full Text »    PDF »
The Structure of the Lingo-1 Ectodomain, a Module Implicated in Central Nervous System Repair Inhibition.
L. Mosyak, A. Wood, B. Dwyer, M. Buddha, M. Johnson, A. Aulabaugh, X. Zhong, E. Presman, S. Benard, K. Kelleher, et al. (2006)
J. Biol. Chem. 281, 36378-36390
   Abstract »    Full Text »    PDF »
Structure of the Cadherin-related Neuronal Receptor/Protocadherin-{alpha} First Extracellular Cadherin Domain Reveals Diversity across Cadherin Families.
H. Morishita, M. Umitsu, Y. Murata, N. Shibata, K. Udaka, Y. Higuchi, H. Akutsu, T. Yamaguchi, T. Yagi, and T. Ikegami (2006)
J. Biol. Chem. 281, 33650-33663
   Abstract »    Full Text »    PDF »
Similarities between heterophilic and homophilic cadherin adhesion.
A. K. Prakasam, V. Maruthamuthu, and D. E. Leckband (2006)
PNAS 103, 15434-15439
   Abstract »    Full Text »    PDF »
N-Glycosylation Affects the Molecular Organization and Stability of E-cadherin Junctions.
A. Liwosz, T. Lei, and M. A. Kukuruzinska (2006)
J. Biol. Chem. 281, 23138-23149
   Abstract »    Full Text »    PDF »
The Crystal Structure of the Primary Ca2+ Sensor of the Na+/Ca2+ Exchanger Reveals a Novel Ca2+ Binding Motif.
D. A. Nicoll, M. R. Sawaya, S. Kwon, D. Cascio, K. D. Philipson, and J. Abramson (2006)
J. Biol. Chem. 281, 21577-21581
   Abstract »    Full Text »    PDF »
Endocytosis of Cadherin from Intracellular Junctions Is the Driving Force for Cadherin Adhesive Dimer Disassembly.
R. B. Troyanovsky, E. P. Sokolov, and S. M. Troyanovsky (2006)
Mol. Biol. Cell 17, 3484-3493
   Abstract »    Full Text »    PDF »
The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15..
Z. M. Ahmed, R. Goodyear, S. Riazuddin, A. Lagziel, P. K. Legan, M. Behra, S. M. Burgess, K. S. Lilley, E. R. Wilcox, S. Riazuddin, et al. (2006)
J. Neurosci. 26, 7022-7034
   Abstract »    Full Text »    PDF »
Studying the Protein Organization of the Postsynaptic Density by a Novel Solid Phase- and Chemical Cross-linking-based Technology.
S.-H. Liu, H.-H. Cheng, S.-Y. Huang, P.-C. Yiu, and Y.-C. Chang (2006)
Mol. Cell. Proteomics 5, 1019-1032
   Abstract »    Full Text »    PDF »
From the Cover: Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques.
A. P. Wiita, S. R. K. Ainavarapu, H. H. Huang, and J. M. Fernandez (2006)
PNAS 103, 7222-7227
   Abstract »    Full Text »    PDF »
The Structure of Leishmania mexicana ICP Provides Evidence for Convergent Evolution of Cysteine Peptidase Inhibitors.
B. O. Smith, N. C. Picken, G. D. Westrop, K. Bromek, J. C. Mottram, and G. H. Coombs (2006)
J. Biol. Chem. 281, 5821-5828
   Abstract »    Full Text »    PDF »
Prototypical Type I E-cadherin and Type II Cadherin-7 Mediate Very Distinct Adhesiveness through Their Extracellular Domains.
Y.-S. Chu, O. Eder, W. A. Thomas, I. Simcha, F. Pincet, A. Ben-Ze'ev, E. Perez, J. P. Thiery, and S. Dufour (2006)
J. Biol. Chem. 281, 2901-2910
   Abstract »    Full Text »    PDF »
Regulation of N-Cadherin Dynamics at Neuronal Contacts by Ligand Binding and Cytoskeletal Coupling.
O. Thoumine, M. Lambert, R.-M. Mege, and D. Choquet (2006)
Mol. Biol. Cell 17, 862-875
   Abstract »    Full Text »    PDF »
Hyper-adhesion in desmosomes: its regulation in wound healing and possible relationship to cadherin crystal structure.
D. R. Garrod, M. Y. Berika, W. F. Bardsley, D. Holmes, and L. Tabernero (2005)
J. Cell Sci. 118, 5743-5754
   Abstract »    Full Text »    PDF »
P-Cadherin Promotes Cell-Cell Adhesion and Counteracts Invasion in Human Melanoma.
V. Van Marck, C. Stove, K. Van Den Bossche, V. Stove, J. Paredes, Y. Vander Haeghen, and M. Bracke (2005)
Cancer Res. 65, 8774-8783
   Abstract »    Full Text »    PDF »
Myosin 2 Is a Key Rho Kinase Target Necessary for the Local Concentration of E-Cadherin at Cell-Cell Contacts.
A. M. Shewan, M. Maddugoda, A. Kraemer, S. J. Stehbens, S. Verma, E. M. Kovacs, and A. S. Yap (2005)
Mol. Biol. Cell 16, 4531-4542
   Abstract »    Full Text »    PDF »
Cadherin adhesion depends on a salt bridge at the N-terminus.
O. J. Harrison, E. M. Corps, and P. J. Kilshaw (2005)
J. Cell Sci. 118, 4123-4130
   Abstract »    Full Text »    PDF »
Critical Role of the Fifth Domain of E-Cadherin for Heterophilic Adhesion with {alpha}E{beta}7, But Not for Homophilic Adhesion.
K. Shiraishi, K. Tsuzaka, K. Yoshimoto, C. Kumazawa, K. Nozaki, T. Abe, K. Tsubota, and T. Takeuchi (2005)
J. Immunol. 175, 1014-1021
   Abstract »    Full Text »    PDF »
Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through {beta}-strand swapping.
C. P. Chen, S. Posy, A. Ben-Shaul, L. Shapiro, and B. H. Honig (2005)
PNAS 102, 8531-8536
   Abstract »    Full Text »    PDF »
Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature.
C. May, J. F. Doody, R. Abdullah, P. Balderes, X. Xu, C. P. Chen, Z. Zhu, L. Shapiro, P. Kussie, D. J. Hicklin, et al. (2005)
Blood 105, 4337-4344
   Abstract »    Full Text »    PDF »
Identification and preliminary characterization of cell-wall-anchored proteins of Staphylococcus epidermidis.
M. G. Bowden, W. Chen, J. Singvall, Y. Xu, S. J. Peacock, V. Valtulina, P. Speziale, and M. Hook (2005)
Microbiology 151, 1453-1464
   Abstract »    Full Text »    PDF »
{gamma}-Protocadherins, Presenilin-mediated Release of C-terminal Fragment Promotes Locus Expression.
B. Hambsch, V. Grinevich, P. H. Seeburg, and M. K. Schwarz (2005)
J. Biol. Chem. 280, 15888-15897
   Abstract »    Full Text »    PDF »
Active participation of endothelial cells in inflammation.
J. M. Cook-Mills and T. L. Deem (2005)
J. Leukoc. Biol. 77, 487-495
   Abstract »    Full Text »    PDF »
Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome).
K W Kjaer, L Hansen, G C Schwabe, A P Marques-de-Faria, H Eiberg, S Mundlos, N Tommerup, and T Rosenberg (2005)
J. Med. Genet. 42, 292-298
   Abstract »    Full Text »    PDF »
Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes.
Q. Wu (2005)
Genetics 169, 2179-2188
   Abstract »    Full Text »    PDF »
The mechanism of cell adhesion by classical cadherins: the role of domain 1.
O. J. Harrison, E. M. Corps, T. Berge, and P. J. Kilshaw (2005)
J. Cell Sci. 118, 711-721
   Abstract »    Full Text »    PDF »
The Conserved Immunoglobulin Domain Controls the Subcellular Localization of the Homophilic Adhesion Receptor Protein-tyrosine Phosphatase {micro}.
R. L. Del Vecchio and N. K. Tonks (2005)
J. Biol. Chem. 280, 1603-1612
   Abstract »    Full Text »    PDF »
The Minimal Essential Unit for Cadherin-mediated Intercellular Adhesion Comprises Extracellular Domains 1 and 2.
W. Shan, Y. Yagita, Z. Wang, A. Koch, A. F. Svenningsen, E. Gruzglin, L. Pedraza, and D. R. Colman (2004)
J. Biol. Chem. 279, 55914-55923
   Abstract »    Full Text »    PDF »
Mechanisms of Blister Formation by Staphylococcal Toxins.
Y. Hanakawa and J. R. Stanley (2004)
J. Biochem. 136, 747-750
   Abstract »    Full Text »    PDF »
Trans-bonded pairs of E-cadherin exhibit a remarkable hierarchy of mechanical strengths.
E. Perret, A. Leung, H. Feracci, and E. Evans (2004)
PNAS 101, 16472-16477
   Abstract »    Full Text »    PDF »
Oncotic pressures opposing filtration across non-fenestrated rat microvessels.
R. H. Adamson, J. F. Lenz, X. Zhang, G. N. Adamson, S. Weinbaum, and F. E. Curry (2004)
J. Physiol. 557, 889-907
   Abstract »    Full Text »    PDF »
VE-cadherin: adhesion at arm's length.
P. A. Vincent, K. Xiao, K. M. Buckley, and A. P. Kowalczyk (2004)
Am J Physiol Cell Physiol 286, C987-C997
   Abstract »    Full Text »    PDF »
Enzymatic and Molecular Characteristics of the Efficiency and Specificity of Exfoliative Toxin Cleavage of Desmoglein 1.
Y. Hanakawa, N. M. Schechter, C. Lin, K. Nishifuji, M. Amagai, and J. R. Stanley (2004)
J. Biol. Chem. 279, 5268-5277
   Abstract »    Full Text »    PDF »
A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells.
B. K. Straub, J. Boda, C. Kuhn, M. Schnoelzer, U. Korf, T. Kempf, H. Spring, M. Hatzfeld, and W. W. Franke (2003)
J. Cell Sci. 116, 4985-4995
   Abstract »    Full Text »    PDF »
Identification of a Surface for Binding to the GDNF-GFR{alpha}1 Complex in the First Cadherin-like Domain of RET.
S. Kjaer and C. F. Ibanez (2003)
J. Biol. Chem. 278, 47898-47904
   Abstract »    Full Text »    PDF »
Adhesive and Lateral E-Cadherin Dimers Are Mediated by the Same Interface.
R. B. Troyanovsky, E. Sokolov, and S. M. Troyanovsky (2003)
Mol. Cell. Biol. 23, 7965-7972
   Abstract »    Full Text »    PDF »
Untangling Desmosomal Knots with Electron Tomography.
W. He, P. Cowin, and D. L. Stokes (2003)
Science 302, 109-113
   Abstract »    Full Text »    PDF »
Characterization of Cadherin-24, a Novel Alternatively Spliced Type II Cadherin.
B. J. Katafiasz, M. T. Nieman, M. J. Wheelock, and K. R. Johnson (2003)
J. Biol. Chem. 278, 27513-27519
   Abstract »    Full Text »    PDF »
Induction of Pemphigus Phenotype by a Mouse Monoclonal Antibody Against the Amino-Terminal Adhesive Interface of Desmoglein 3.
K. Tsunoda, T. Ota, M. Aoki, T. Yamada, T. Nagai, T. Nakagawa, S. Koyasu, T. Nishikawa, and M. Amagai (2003)
J. Immunol. 170, 2170-2178
   Abstract »    Full Text »    PDF »
Nectin and afadin: novel organizers of intercellular junctions.
Y. Takai and H. Nakanishi (2003)
J. Cell Sci. 116, 17-27
   Abstract »    Full Text »    PDF »
In the First Extracellular Domain of E-cadherin, Heterophilic Interactions, but Not the Conserved His-Ala-Val Motif, Are Required for Adhesion.
M. Renaud-Young and W. J. Gallin (2002)
J. Biol. Chem. 277, 39609-39616
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)