Structural and energetic determinants of adhesive binding specificity in type I cadherins

• DOI: 10.1073/pnas.1416737111
• Publication Date: 2014-09-25T06:05:57Z
• Authors: Jeremie Vendome; Klara Felsovalyi; Hang Song; Zhongyu Yang; Xiangshu Jin; Julia Brasch; Oliver J. Harrison; Goran Ahlsen; Fabiana Bahna; Anna Kaczynska; Phinikoula S. Kat...; Darwin Edmond; Wayne L. Hubbell; Lawrence Shapiro; Barry Honig
• Keywords: Models, Molecular; Protein Structure; Secondary; 1.1 Normal biological development and functioning; Xenopus; Molecular Sequence Data; Static Electricity; Sequence Homology; entropy contribution; Xenopus Proteins; protein family design; Crystallography, X-Ray; Binding, Competitive; Protein Structure, Secondary; Mice; 03 medical and health sciences; Competitive; Underpinning research; Models; Animals; Humans; Amino Acid Sequence; 0303 health sciences; Crystallography; Sequence Homology, Amino Acid; Electron Spin Resonance Spectroscopy; Molecular; Binding; cadherin dimerization; Cadherins; Protein Structure, Tertiary; Amino Acid; Kinetics; Emerging Infectious Diseases; HEK293 Cells; Mutation; X-Ray; Protein Multimerization; Hydrophobic and Hydrophilic Interactions; Tertiary; Biotechnology; Protein Binding

Significance Type I cadherins comprise a family of cell–cell adhesion proteins that dimerize in a highly specific fashion. There are small differences in dimerization affinities among family members that are evolutionarily conserved and that have profound effects on cell-patterning behavior. There are few examples where the molecular origins of small affinity differences between closely related proteins have been explored in depth. We have brought an unusually broad range of technologies to bear on the problem in a unique integrated approach. Our results reveal how a subtle combination of physical interactions combine to tune binding affinities and, in the course of our analysis, we discover a new conformational entropy-based mechanism that can also be exploited by other multidomain proteins.