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Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):E4175-84. doi: 10.1073/pnas.1416737111. Epub 2014 Sep 24.

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

Author information

1
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;
2
Jules Stein Eye Institute and.
3
Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
4
Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Department of Systems Biology.
5
Department of Physics, University of Washington, Seattle, WA 98195; and.
6
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.
7
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.
8
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.

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.

KEYWORDS:

cadherin dimerization; entropy contribution; protein family design

PMID:
25253890
PMCID:
PMC4210030
DOI:
10.1073/pnas.1416737111
[Indexed for MEDLINE]
Free PMC Article

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