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Molecular plasticity of -catenin: New insights from single-molecule measurements and MD simulation

¹ London Centre for Nanotechnology and Department of Medicine, University College London, London WC1E 6JJ, United Kingdom
² Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom

(RECEIVED January 15, 2007; FINAL REVISION May 2, 2007; ACCEPTED May 14, 2007)

The multifunctional protein, -catenin, has essential roles in cell adhesion and, through the Wnt signaling pathway, in controlling cell differentiation, development, and generation of cancer. Could distinct molecular forms of -catenin underlie these two functions? Our single-molecule force spectroscopy of armadillo -catenin, with molecular dynamics (MD) simulation, suggests a model in which the cell generates various forms of -catenin, in equilibrium. We find -catenin and the transcriptional factor Tcf4 form two complexes with different affinities. Specific cellular response is achieved by the ligand binding to a particular matching preexisting conformer. Our MD simulation indicates that complexes derive from two conformers of the core region of the protein, whose preexisting molecular forms could arise from small variations in flexible regions of the -catenin main binding site. This mechanism for the generation of the various forms offers a route to tailoring future therapeutic strategies.

Keywords: atomic force microscopy; -catenin; ICAT; MD simulation; Wnt signaling

Reprint requests to: Michael Horton, London Centre for Nanotechnology and Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK; e-mail: m.horton{at}ucl.ac.uk; fax: 44-020-7679-6219.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.072773007.

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