Shapiro Lab
CADHERINS 

     Cadherins are thought to be the primary mediators of adhesion between the cells of vertebrate animals, and also function in cell adhesion in many invertebrates.   The expression of numerous cadherins during development is highly regulated, and the precise pattern of cadherin expression plays a pivotal role in the morphogenesis of tissues and organs.   Furthermore, cadherins are important in the continued maintenance of tissue structure and integrity, for example loss of cadherin expression appears to be highly correlated with the invasiveness of some types of tumors.   Cell adhesion mediated by cadherins is thought to be homotypic.  That is to say that a cell expressing type X cadherin will associate with another cell expressing cadherin X.   Cadherin adhesion is also dependent on the presence of millimolar calcium ion concentrations, as are found in the extracellular milieu.

    The cadherin protein superfamily, defined as proteins containing a cadherin-like domain, can be divided into several sub-groups.   These include the classical (type I) cadherins, which mediate adhesion at adherens junctions; the highly-related type II cadherins; the desmosomal cadherins found in desmosome junctions; protocadherins, expressed only in the nervous system; and atypical cadherin-like domain containing proteins.   Members of all but the atypical group have been shown to play a role in intercellular adhesion.

    Classical, type II, and desmosomal cadherins share a common domain organization:  Each comprises five tandem extracellular cadherin domains, a single transmembrane segment, and a highly conserved cytoplasmic domain.   The cytoplasmic domains of the classical cadherins, thought to interact with the actin cytoskeleton through specific adaptor proteins, are distinct from those of desmosomal cadherins, which attach to the intermediate filament system.   The protocadherins, which may take part in defining the specificity of synaptic connections between neurons, are encoded in a novel gene locus containing fifty-two single-exon "variable" ectodomain regions, and at least two cytoplasmic domain "constant" regions in humans.   The mature proteins derive from combining the extracellular and cytoplasmic regions through a highly regulated mRNA splicing pathway. Protocadherins contain six tandem cadherin-like domains in the extracellular segment, and each of the known cytoplasmic domains is unrelated to other known proteins.

    High-resolution structural studies have shown that the sequence repeats of cadherin extracellular segments fold into domains with an immunoglobulin-like topology.   The connections between these domains are rigidified by the ligation of three Ca2+ ions by conserved residues at the "bottom" of domain n, the "top" of domain n+1, and the linker segment between them.   Despite the information gained from these structural studies, the central question of cadherin molecular function has remained: What is the atomic-level basis of cadherin function in adhesion?   What intermolecular interface(s) provides the attachment point between cells, and what are the determinants of adhesive specificity?

Strand dimer
    Several intermolecular interfaces have been identified in cadherin crystal structures, and others have been suggested based on mutagenesis data, peptide inhibition studies, and analogy to binding sites in similarly folded immunoglobulin-like domain.   One of these interfaces, observed in the first set of cadherin domain crystal structures, is comprised of a conserved tryptophan side chain (from Trp 2) that intercalates into a conserved hydrophobic pocket in a partner molecule.   This interface, called the "strand dimer" because it involves the symmetrical exchange of N-terminal beta-strands between EC1 domain protomers, has been shown to be essential for cadherin adhesion by site-directed mutagenesis of both Trp 2 and its acceptor pocket.   However, the orientation of protomers in the initial strand dimer structures led to the suggestion that its function would likely involve cis or same-cell interactions rather than trans adhesion between juxtaposing cells.

Crystal lattice
    The vast majority of data suggests that the strand dimer represents the cadherin cell-to-cell adhesive interface. Numerous studies in the lab have now been performed to characterize the biophysics of binding through this interface, as well as other potential interfaces used by cadherins in the formation of junction structures.

 

Publications

Nature
2011; Jul 27;475(7357):510-3
Transforming binding affinities from three dimensions to two with application to cadherin clustering.
Wu Y, Vendome J, Shapiro L, Ben-Shaul A, Honig B.
on-line

Nat Struct Mol Biol
2011; Jun;18(6):693-700
Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins.
Vendome J, Posy S, Jin X, Bahna F, Ahlsen G, Shapiro L, Honig B.
on-line

Struture
2011; Feb 9;19(2):244-56
The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.
Harrison OJ, Jin X, Hong S, Bahna F, Ahlsen G, Brasch J, Wu Y, Vendome J, Felsovalyi K, Hampton CM, Troyanovsky RB, Ben-Shaul A, Frank J, Troyanovsky SM, Shapiro L, Honig B.
on-line

J Mol Biol.
2011;Apr 22;408(1):57-73
Structure and binding mechanism of vascular endothelial cadherin: a divergent classical cadherin.
Brasch J, Harrison OJ, Ahlsen G, Carnally SM, Hederson RM, Honig B, Shapiro L.
on-line

Proc Natl Acad Sci U S A
2010;Oct 12;107(41):17592-7
Cooperativity between trans and cis interactions in cadherin-mediated junction formation.
Wu Y, Jin X, Harrison O, Shapiro L, Honig BH, Ben-Shaul A.
on-line

Neuron
2010;Jul 15;67(1):61-74
Splice Form Dependence of -Neurexin/Neuroligin Binding Interactions
Koehnke J, Katsamba PS, Ahlsen G, Bahna F, Vendome J, Honig B, Shapiro L, Jin X,
on-line

Nat Struct Biol
2010;Feb 28;17(3):339-348
Two-step adhesive binding by classical cadherins
Harrison OJ, Bahna F, Katsamba PS, Jin X, Brasch J, Vendome J, Ahlsen G, Carroll KJ, Price SR, Honig B, Shapiro L
on-line

Nat Struct Biol
2010;Feb 28;17(3):339-348
T-cadherin structure reveal a novel adhesive binding mechanism
Ciatto C, Bahna F, Zampieri N, VanSteenhouse HC, Katsamba PS, Ahlsen G, Harrison OJ, Brasch J, Jin X, Posy S, Vendome J, Ranscht B, Jessell TM, Honig B, Shapiro L
on-line


Structure

2008;Aug 6;16(8):1195-205
Dynamic properties of a type II cadherin adhesive domain: implications for the mechanism of strand-swapping of classical cadherins.
Miloushev VZ, Bahna F, Ciatto C, Ahlsen G, Honig B, Shapiro L, Palmer AG 3rd   
on-line

J Mol Biol
2008;May 9;378(4):954-68
Sequence and structural determinants of strand swapping in cadherin domains: do all cadherins bind through the same adhesive interdace?
Posy S, Shapiro L, Honig B   
on-line

Structure
2008;March 11;16(3);410-421
Crystal structures of β-Neurexin 1 and β-Neurexin 2 Ectodomains and Dynamics of Splice Insertion Sequence 4
Koehnke J, Jin X, Trbovic N, Katsamba PS, Brasch J, Ahlsen G, Scheiffele P, Honig B, Palmer AG 3rd, Shapiro L   
on-line


Proc Natl Acad Sci U S A
2008;Feb 12;105(6);1873-1878
Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2.
Koehnke J, Jin X, Budreck EC, Posy S, Scheiffele P, Honig B, Shapiro L   
on-line


Cell
2006;Mar 24;124(6);1255-68
Type II cadherin ectodomain structures: implications for classical cadherin specifity.
Patel SD, Ciatto C, Chen CP, Bahna F, Rajebhosale M, Arkus N, Schieren I, Jessell TM, Honig B, Price SR, Shapiro L   
on-line


Proc Natl Acad Sci U S A

2005;Jun 14;102(24):8531-6
Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through beta-strand swapping.
Chen CP, Posy S, Ben-Sahul A, Shapiro L, Honig BH   
on-line

Curr Opin Struct Biol
2003;13:690-698
Cadherin-mediated cell-cell adhesion: sticking together as a family.
Patel SD, Chen CP, Bahna F, Honig B, Shapiro L   
on-line

 

Science
2002; May 17;296(5571):1308-13
C-Cadherin Ectodomain Structure and Implications for Cell Adhesion Mechanisms.
Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L
on-line

 

Neuron
2001 Oct 11;32(1):63-77
The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution.
Phillips GR, Huang JK, Wang Y, Tanaka H, Shapiro L, Zhang W, Shan WS, Arndt K, Frank M, Gordon RE, Gawinowicz MA, Zhao Y, Colman DR
on-line

 

Nat Struct Biol
2001 Jun;8(6):484-7
Beta-catenin and its multiple partners: promiscuity explained.
Shapiro L
on-line 

 

Trends Cell Biol
2000 Nov;10(11):473-82
Making memories stick: cell-adhesion molecules in synaptic plasticity.
Benson DL, Schnapp LM, Shapiro L, Huntley GW
on-line

 

Neuron
2000 Jan;25(1):93-107
Molecular modification of N-cadherin in response to synaptic activity.
Tanaka H, Shan W, Phillips GR, Arndt K, Bozdagi O, Shapiro L, Huntley GW, Benson DL, Colman DR
on-line

 

J Cell Biol
2000 Feb 7;148(3):579-90
Functional cis-heterodimers of N- and R-cadherins.
Shan WS, Tanaka H, Phillips GR, Arndt K, Yoshida M, Colman DR, Shapiro L
on-line

 

Biophys Chem
1999 Dec 13;82(2-3):157-63
The adhesive binding site of cadherins revisited.
Shan WS, Koch A, Murray J, Colman DR, Shapiro L
on-line 

 

Neuron
1999 Jul;23(3):427-30
The diversity of cadherins and implications for a synaptic adhesive code in the CNS.
Shapiro L, Colman DR
on-line

 

Curr Opin Neurobiol
1998 Oct;8(5):593-9
Structural biology of cadherins in the nervous system.
Shapiro L, Colman DR
on-line

 

Neuron
1998 Jun;20(6):1153-63
Structure-function analysis of cell adhesion by neural (N-) cadherin.
Tamura K, Shan WS, Hendrickson WA, Colman DR, Shapiro L
on-line 

 

Structure
1997 Oct 15;5(10):1265-8
The multi-talented beta-catenin makes its first appearance.
Shapiro L
on-line 

 

Proc Natl Acad Sci U S A
1995 Jul 18;92(15):6793-7
Considerations on the folding topology and evolutionary origin of cadherin domains.
Shapiro L, Kwong PD, Fannon AM, Colman DR, Hendrickson WA
on-line

 

Nature
1995 Mar 23;374(6520):327-37
Structural basis of cell-cell adhesion by cadherins.
Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als-Nielsen J, Colman DR, Hendrickson WA
on-line

 

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