The Cadherin Superfamily at the Synapse: More Members, More Missions

Abstract

The tripeptide HAV and its flanking amino acid residues in EC1 were originally found to govern binding specificity of E- and P-cadherins, and this strongly suggests that EC1 is involved in homophilic adhesive interactions. Two groups have solved crystal structures of EC1 and/or two-domain EC1-EC2 fragments of classic cadherins (14xShapiro, L, Fannon, A.M, Kwong, P.D, Thompson, A, Lehmann, M.S, Grubel, G, Legrand, J.-F, Als-Nielsen, J, Colman, D.R, and Hendrickson, W.A. Nature. 1995; 374: 327–337Crossref | PubMedSee all References, 11xNagar, B, Overduin, M, Ikura, M, and Rini, J.M. Nature. 1996; 380: 360–364Crossref | PubMed | Scopus (466)See all References, 16xTamura, K, Shan, W.-S, Hendrickson, W.A, Colman, D.R, and Shapiro, L. Neuron. 1998; 20: 1153–1163Abstract | Full Text | Full Text PDF | PubMed | Scopus (239)See all References), and two forms of EC1 dimers of N-cadherin have attracted attention: the strand dimer and the adhesion dimer (Figure 2Figure 2A). The adhesion dimer was named after an anti-parallel alignment of protomers from opposing cell surfaces, whereas the strand dimer is made by lateral association. Tamura et al. demonstrated that the adhesion ability is completely abolished by mutating residues located in the strand dimer interface (Tamura et al. 1998xTamura, K, Shan, W.-S, Hendrickson, W.A, Colman, D.R, and Shapiro, L. Neuron. 1998; 20: 1153–1163Abstract | Full Text | Full Text PDF | PubMed | Scopus (239)See all ReferencesTamura et al. 1998). To explain the molecular basis for cadherin-mediated strong adhesiveness, they discussed the cis dimerization model in which a monomeric form may be inactive for cell adhesion and the cis dimerization may be a key regulatory step to produce an active conformation (Figure 2Figure 2A). One line of supportive evidence comes from observation of recombinant extracellular domains by electron microscopy, which suggested that cis pairing of EC1 takes place first, followed by trans interaction, and that none of the other four ECs are involved in this two-step binding (Tomschy et al. 1996xTomschy, A, Fauser, C, Landwehr, R, and Engel, J. EMBO J. 1996; 15: 3507–3514PubMedSee all ReferencesTomschy et al. 1996). It should be stressed that not only lateral interaction of EC1, but also cytoplasmic clustering contributes to the strengthening of adhesion (Yap et al. 1998xYap, A.S, Niessen, C.M, and Gumbiner, B.M. J. Cell Biol. 1998; 141: 779–789Crossref | PubMed | Scopus (405)See all ReferencesYap et al. 1998references therein).Figure 2Dynamic Equilibrium between Inactive Monomeric and Active Dimeric Forms of the Classic Cadherin (A) and the Largest Molecule of the Cadherin Superfamily, Fat (B)(A) The strand dimer and the adhesion dimer represent two different forms of the EC1 crystal and they are shaded more darkly than the other ECs. This diagram was made on the basis of studies on three distinct cadherins.(B) The Fat protein, encoded by a Drosophila tumor suppressor gene, has 34 tandem ECs and is drawn on the same scale used in (A). The circles represent the laminin A–like globular domains and the cross-hatched box, EGF-like repeat. The tertiary structure of Fat has not yet been reported.View Large Image | View Hi-Res Image | Download PowerPoint SlideCompared to the classic cadherins, CNR and protocadherin have extra copies of EC and some of the other members of the superfamily are of an enormous size (Figure 2Figure 2B; for example, seeMahoney et al. 1991xMahoney, P.A, Weber, U, Onofrechuk, P, Biessman, H, Bryant, P.J, and Goodman, C.S. Cell. 1991; 67: 853–868Abstract | Full Text PDF | PubMedSee all ReferencesMahoney et al. 1991). Is the cis dimerization model applicable throughout the superfamily with such structural variety? How are such molecules with so many tandem ECs folded and crammed into the intercellular space? One of those large proteins is D N-cadherin with 15 ECs (Iwai et al. 1997xIwai, Y, Usui, T, Hirano, S, Steward, R, Takeichi, M, and Uemura, T. Neuron. 1997; 19: 77–89Abstract | Full Text | Full Text PDF | PubMed | Scopus (208)See all ReferencesIwai et al. 1997). Curiously, its extracellular portion appears to be cleaved at a position proximal to the transmembrane segment; nonetheless, two polypeptides generated associate with each other. Posttranslational processing of this kind might be one way to confer a three-dimensional conformation appropriate for its molecular function and might hold true for the other giant molecules of invertebrates and vertebrates. Which of the 15 ECs of D N-cadherin participates in the adhesive binding is still an open question.In sum, the cadherin superfamily is expanding, stereo views of molecules are becoming more divergent, and overall, this family is being found to perform more, previously unrecognized missions at intercellular junctions.