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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Intercellular Interactions Study Section (ICI)
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Flicker, Paula F
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Columbia University (N.Y.)
Schools of Medicine
New York
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Rubinstein, Rotem; Goodman, Kerry Marie; Maniatis, Tom et al. (2017) Structural origins of clustered protocadherin-mediated neuronal barcoding. Semin Cell Dev Biol 69:140-150
Goodman, Kerry Marie; Rubinstein, Rotem; Thu, Chan Aye et al. (2016) ?-Protocadherin structural diversity and functional implications. Elife 5:
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Goodman, Kerry Marie; Rubinstein, Rotem; Thu, Chan Aye et al. (2016) Structural Basis of Diverse Homophilic Recognition by Clustered ?- and ?-Protocadherins. Neuron 90:709-23
Chen, Chi-Shuo; Hong, Soonjin; Indra, Indrajyoti et al. (2015) ?-Catenin-mediated cadherin clustering couples cadherin and actin dynamics. J Cell Biol 210:647-61
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Rubinstein, Rotem; Thu, Chan Aye; Goodman, Kerry Marie et al. (2015) Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell 163:629-42
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

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