title: Structural and thermodynamic characterization of cadherin·β-catenin·α-catenin complex formation.
abstract: The classical cadherin·β-catenin·α-catenin complex mediates homophilic cell-cell adhesion and mechanically couples the actin cytoskeletons of adjacent cells. Although α-catenin binds to β-catenin and to F-actin, β-catenin significantly weakens the affinity of α-catenin for F-actin. Moreover, α-catenin self-associates into homodimers that block β-catenin binding. We investigated quantitatively and structurally αE- and αN-catenin dimer formation, their interaction with β-catenin and the cadherin·β-catenin complex, and the effect of the α-catenin actin-binding domain on β-catenin association. The two α-catenin variants differ in their self-association properties: at physiological temperatures, αE-catenin homodimerizes 10× more weakly than does αN-catenin but is kinetically trapped in its oligomeric state. Both αE- and αN-catenin bind to β-catenin with a Kd of 20 nM, and this affinity is increased by an order of magnitude when cadherin is bound to β-catenin. We describe the crystal structure of a complex representing the full β-catenin·αN-catenin interface. A three-dimensional model of the cadherin·β-catenin·α-catenin complex based on these new structural data suggests mechanisms for the enhanced stability of the ternary complex. The C-terminal actin-binding domain of α-catenin has no influence on the interactions with β-catenin, arguing against models in which β-catenin weakens actin binding by stabilizing inhibitory intramolecular interactions between the actin-binding domain and the rest of α-catenin.
authors.affiliation: From the Departments of Structural Biology and Molecular and Cellular Physiology, Stanford University, Stanford, California 94305.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pokutta
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Goran
authors.initials: G
authors.lastname: Ahlsen
authors.forename: Scott D
authors.initials: SD
authors.lastname: Hansen
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
mesh_terms: D000818:Animals; D015820:Cadherins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D013816:Thermodynamics; D051178:alpha Catenin / Q000737:chemistry*; D051176:beta Catenin / Q000737:chemistry*
chemical_list: D015820:Cadherins; D046912:Multiprotein Complexes; D051178:alpha Catenin; D051176:beta Catenin
keywords: Analytical Ultracentrifugation; Cadherins; Cell Adhesion; Isothermal Titration Calorimetry; X-ray Crystallography; α-Catenin; β-Catenin