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Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis

View ORCID ProfileJohn M. Nicoludis, View ORCID ProfileAnna G. Green, Sanket Walujkar, View ORCID ProfileElizabeth J. May, Marcos Sotomayor, Debora S. Marks, View ORCID ProfileRachelle Gaudet
doi: https://doi.org/10.1101/493106
John M. Nicoludis
1Department of Molecular and Cellular Biology, Harvard University, Cambridge MA, USA
2Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
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  • ORCID record for John M. Nicoludis
Anna G. Green
3Department of Systems Biology, Harvard Medical School, Boston, MA, USA
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Sanket Walujkar
4Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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Elizabeth J. May
1Department of Molecular and Cellular Biology, Harvard University, Cambridge MA, USA
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Marcos Sotomayor
4Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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Debora S. Marks
3Department of Systems Biology, Harvard Medical School, Boston, MA, USA
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  • For correspondence: debbie@hms.harvard.edu gaudet@mcb.harvard.edu
Rachelle Gaudet
1Department of Molecular and Cellular Biology, Harvard University, Cambridge MA, USA
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  • ORCID record for Rachelle Gaudet
  • For correspondence: debbie@hms.harvard.edu gaudet@mcb.harvard.edu
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Abstract

Clustered protocadherins are a large family of paralogous proteins that play important roles in neuronal development. The more than 50 clustered protocadherin isoforms have remarkable homophilic specificity for interactions between cellular surfaces that is controlled by a large antiparallel dimer interface formed by the first four extracellular cadherin (EC) domains. To understand how specificity is achieved between the numerous paralogs, we used a combination of structural and computational approaches. Molecular dynamics simulations revealed that individual EC interactions are weak and go through binding and unbinding events, but together they form a stable complex through polyvalency. Using sequence coevolution, we generated a statistical model of interaction energy for the clustered protocadherin family that measures the contributions of all amino acid pairs in the interface. Our interaction energy model assesses specificity for all possible pairs of isoforms, recapitulating known pairings and predicting the effects of experimental changes in isoform specificity that are consistent with literature results. Our results show that sequence coevolution can be used to understand specificity determinants in a protein family and prioritize interface amino acid substitutions to reprogram specific protein-protein interactions.

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Posted December 11, 2018.
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Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis
John M. Nicoludis, Anna G. Green, Sanket Walujkar, Elizabeth J. May, Marcos Sotomayor, Debora S. Marks, Rachelle Gaudet
bioRxiv 493106; doi: https://doi.org/10.1101/493106
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Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis
John M. Nicoludis, Anna G. Green, Sanket Walujkar, Elizabeth J. May, Marcos Sotomayor, Debora S. Marks, Rachelle Gaudet
bioRxiv 493106; doi: https://doi.org/10.1101/493106

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