Molecular plasticity of beta-catenin: new insights from single-molecule measurements and MD simulation.
The multifunctional protein, beta-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 beta-catenin underlie these two functions? Our single-molecule force spectroscopy of armadillo beta-catenin, with molecular dynamics (MD) simulation, suggests a model in which the cell generates various forms of beta-catenin, in equilibrium. We find beta-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 beta-catenin main binding site. This mechanism for the generation of the various forms offers a route to tailoring future therapeutic strategies.
London Centre for Nanotechnology and Department of Medicine, University College London, London WC1E 6JJ, United Kingdom.
Monica
M
Ritco-Vonsovici
Abdessamad
A
Ababou
Michael
M
Horton
D000538:Aluminum Silicates / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D005982:Glutathione Transferase / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013499:Surface Properties; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D000538:Aluminum Silicates; D008024:Ligands; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D006639:Histidine; D006735:Horseradish Peroxidase; D005982:Glutathione Transferase; C011934:mica