title: Structural and energetic determinants of adhesive binding specificity in type I cadherins.
abstract: Type I cadherin cell-adhesion proteins are similar in sequence and structure and yet are different enough to mediate highly specific cell-cell recognition phenomena. It has previously been shown that small differences in the homophilic and heterophilic binding affinities of different type I family members can account for the differential cell-sorting behavior. Here we use a combination of X-ray crystallography, analytical ultracentrifugation, surface plasmon resonance and double electron-electron resonance (DEER) electron paramagnetic resonance spectroscopy to identify the molecular determinants of type I cadherin dimerization affinities. Small changes in sequence are found to produce subtle structural and dynamical changes that impact relative affinities, in part via electrostatic and hydrophobic interactions, and in part through entropic effects because of increased conformational heterogeneity in the bound states as revealed by DEER distance mapping in the dimers. These findings highlight the remarkable ability of evolution to exploit a wide range of molecular properties to produce closely related members of the same protein family that have affinity differences finely tuned to mediate their biological roles.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Jeremie
authors.initials: J
authors.lastname: Vendome
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Klara
authors.initials: K
authors.lastname: Felsovalyi
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Hang
authors.initials: H
authors.lastname: Song
authors.affiliation: Jules Stein Eye Institute and.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology.
authors.forename: Julia
authors.initials: J
authors.lastname: Brasch
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Harrison
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Goran
authors.initials: G
authors.lastname: Ahlsen
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bahna
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaczynska
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Phinikoula S
authors.initials: PS
authors.lastname: Katsamba
authors.affiliation: Department of Physics, University of Washington, Seattle, WA 98195; and.
authors.forename: Darwin
authors.initials: D
authors.lastname: Edmond
authors.affiliation: Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095 hubbellw@jsei.ucla.edu lss8@columbia.edu bh6@columbia.edu.
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hubbell
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, hubbellw@jsei.ucla.edu lss8@columbia.edu bh6@columbia.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology, Howard Hughes Medical Institute, Columbia University, New York, NY 10032; hubbellw@jsei.ucla.edu lss8@columbia.edu bh6@columbia.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D014981:Xenopus; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D029867:Xenopus Proteins
keywords: cadherin dimerization; entropy contribution; protein family design