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Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads

Huy Nguyen, Jagoree Roy, Björn Harink, Nikhil Damle, Brian Baxter, Kara Brower, Tanja Kortemme, Kurt Thorn, Martha Cyert, View ORCID ProfilePolly Fordyce
doi: https://doi.org/10.1101/306779
Huy Nguyen
1Department of Genetics, Stanford University, Stanford, CA 94305
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Jagoree Roy
2Department of Biology, Stanford University, Stanford, CA 94305
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Björn Harink
1Department of Genetics, Stanford University, Stanford, CA 94305
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Nikhil Damle
2Department of Biology, Stanford University, Stanford, CA 94305
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Brian Baxter
3Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA 94158
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Kara Brower
5Department of Bioengineering, Stanford University, Stanford, CA 94305
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Tanja Kortemme
6Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158
7Chan Zuckerberg Biohub, San Francisco, CA 94158
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Kurt Thorn
4Zymergen, Inc., San Francisco, CA
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Martha Cyert
2Department of Biology, Stanford University, Stanford, CA 94305
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Polly Fordyce
1Department of Genetics, Stanford University, Stanford, CA 94305
5Department of Bioengineering, Stanford University, Stanford, CA 94305
7Chan Zuckerberg Biohub, San Francisco, CA 94158
8eChEM-H Institute, Stanford University, Stanford, CA 94305
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  • ORCID record for Polly Fordyce
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Abstract

Transient, regulated binding of globular protein domains to Short Linear Motifs (SLiMs) in disordered regions of other proteins drives cellular signaling. Mapping the energy landscapes of these interactions is essential for deciphering and therapeutically perturbing signaling networks, but is challenging due to their weak affinities. We present a powerful technology, MRBLE-pep, that simultaneously quantifies protein binding to a library of peptides directly synthesized on beads containing unique spectral codes. Using computational modeling and MRBLE-pep, we systematically probe binding of calcineurin (CN), a conserved protein phosphatase essential for the immune response and target of immunosuppressants, to the PxIxIT SLiM. We establish that flanking residues and post- translational modifications critically contribute to PxIxIT-CN affinity, and discover CN-inhibitory peptides with unprecedented affinity and therapeutic potential. The quantitative measurements provided by this approach will improve computational modeling efforts, elucidate a broad range of weak protein-SLiM interactions, and revolutionize our understanding of signaling networks.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 04, 2018.
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Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads
Huy Nguyen, Jagoree Roy, Björn Harink, Nikhil Damle, Brian Baxter, Kara Brower, Tanja Kortemme, Kurt Thorn, Martha Cyert, Polly Fordyce
bioRxiv 306779; doi: https://doi.org/10.1101/306779
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Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads
Huy Nguyen, Jagoree Roy, Björn Harink, Nikhil Damle, Brian Baxter, Kara Brower, Tanja Kortemme, Kurt Thorn, Martha Cyert, Polly Fordyce
bioRxiv 306779; doi: https://doi.org/10.1101/306779

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