Cadherins are among the most important and widely distributed cell adhesion proteins, and their selective binding helps to define physical connections between the cells of vertebrates and invertebrates. Cadherin selectivity provides a critical mechanism to shape developing tissues. In earlier work, we defined the atomic-level molecular mechanisms of vertebrate classical cadherin adhesive interaction and junction formation. Here we propose specific aims in three main areas to build on this work: (1) we will quantitatively determine the affinities of interactions among the classical cadherins, and define cellular correlates of these molecular properties. (2) We will investigate structural and mechanistic aspects of adherens junctions, and (3) we will determine structures and binding mechanisms for Drosophila classical cadherins in order to develop a facile genetic system with which the molecular adhesive properties of cadherins can be tested for their effects on tissue development.

Public Health Relevance

Cadherins mediate adhesion between cells to help form and hold together the solid tissues of the body. Our proposed work will provide a mechanistic understanding of their function and quantitative measures of their interactions. These data will help to understand in unprecedented detail how cell adhesion helps shape the body plan.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062270-11
Application #
8450697
Study Section
Intercellular Interactions (ICI)
Program Officer
Flicker, Paula F
Project Start
2001-07-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$310,156
Indirect Cost
$116,309
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Vendome, Jeremie; Felsovalyi, Klara; Song, Hang et al. (2014) Structural and energetic determinants of adhesive binding specificity in type I cadherins. Proc Natl Acad Sci U S A 111:E4175-84
Li, Ying; Altorelli, Nicole L; Bahna, Fabiana et al. (2013) Mechanism of E-cadherin dimerization probed by NMR relaxation dispersion. Proc Natl Acad Sci U S A 110:16462-7
Wu, Wei; Ahlsen, Goran; Baker, David et al. (2012) Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. Neuron 74:261-8
Jin, Xiangshu; Walker, Melissa A; Felsövályi, Klára et al. (2012) Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca²+-free interdomain linkers. Proc Natl Acad Sci U S A 109:E127-34
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Brasch, Julia; Harrison, Oliver J; Ahlsen, Goran et al. (2011) Structure and binding mechanism of vascular endothelial cadherin: a divergent classical cadherin. J Mol Biol 408:57-73
Wu, Yinghao; Vendome, Jeremie; Shapiro, Lawrence et al. (2011) Transforming binding affinities from three dimensions to two with application to cadherin clustering. Nature 475:510-3
Vendome, Jeremie; Posy, Shoshana; Jin, Xiangshu et al. (2011) Molecular design principles underlying ?-strand swapping in the adhesive dimerization of cadherins. Nat Struct Mol Biol 18:693-700
Brasch, Julia; Harrison, Oliver J; Ahlsen, Goran et al. (2011) Crystal structure of the ligand binding domain of netrin G2. J Mol Biol 414:723-34
Demireva, Elena Y; Shapiro, Lawrence S; Jessell, Thomas M et al. (2011) Motor neuron position and topographic order imposed by ýý- and ýý-catenin activities. Cell 147:641-52

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