The binding of cadherins from apposing cell surfaces drives the development of organized multicellular structures. However, the physical basis for cadherin function, especially the differential binding specificities of the nineteen classical (type I and type II) cadherins, and the role of the unique GPI-anchored T-cadherin that functions in concert with them, remain poorly understood. The goals of this proposal are to provide a molecular, structural, and energetic view of classical cadherin function and to relate binding specificity at the molecular level to adhesive specificity at the cellular level. In the past funding period we made significant progress on these questions (a) by solving the first crystal structure of a complete type I cadherin ectodomain;(b) by solving the first crystal structures of type II cadherins;(c) by clearly establishing the role of 2-strand swapping in the EC1 cadherin ectodomain as the primary structural mechanism underlying classical cadherin binding specificity;(d) by developing in-vivo assays for type II cadherin function;(e) by showing that a single hydrogen bond can determine binding specificity between type I cadherins;and (f) by solving the first crystal structures of T-cadherin, showing that this non-classical cadherin functions by a novel mechanism. These advances provide much of the basis for the specific aims of the current proposal. We will (Aim 1) Determine binding affinities for an all-against-all matrix of classical cadherins and T-cadherin, and (Aim 2) employ our structural understanding of cadherins to design and characterize cadherin mutants with altered adhesive specificities. These studies will provide an improved understanding of the relationship between cadherin binding affinities and the adhesive behavior of cells, shedding new light on the functional implications of cadherin expression patterns observed in vertebrate development. Because cadherins are involved in the development of virtually all multicellular structures in vertebrate animals, their function and dysfunction have broad impact on human health. Mutations in cadherins are the underlying cause of many heritable defects. Loss of cadherin function, allowing tumor cells to de- adhere and become mobile in the body, is thought to be a prerequisite for metastasis of some forms of cancer. The research we propose will produce a comprehensive atomic-level understanding of cadherins that will be critical in understanding cadherin-related genetic disorders and can provide a basis for the development of small molecule drugs selective for inhibition of individual cadherins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062270-09
Application #
8006409
Study Section
Intercellular Interactions (ICI)
Program Officer
Flicker, Paula F
Project Start
2001-07-01
Project End
2012-03-31
Budget Start
2010-12-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$294,326
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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:
Harrison, Oliver J; Brasch, Julia; Lasso, Gorka et al. (2016) Structural basis of adhesive binding by desmocollins and desmogleins. Proc Natl Acad Sci U S A 113:7160-5
Goodman, Kerry M; Yamagata, Masahito; Jin, Xiangshu et al. (2016) Molecular basis of sidekick-mediated cell-cell adhesion and specificity. Elife 5:
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
Biswas, Kabir H; Hartman, Kevin L; Yu, Cheng-han et al. (2015) E-cadherin junction formation involves an active kinetic nucleation process. Proc Natl Acad Sci U S A 112:10932-7
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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