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Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions

Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZ...

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Autores principales: Potapov, Vladimir, Kaplan, Jenifer B., Keating, Amy E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335062/
https://www.ncbi.nlm.nih.gov/pubmed/25695764
http://dx.doi.org/10.1371/journal.pcbi.1004046
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author Potapov, Vladimir
Kaplan, Jenifer B.
Keating, Amy E.
author_facet Potapov, Vladimir
Kaplan, Jenifer B.
Keating, Amy E.
author_sort Potapov, Vladimir
collection PubMed
description Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZIP proteins has been intensively studied, and a variety of methods have been proposed to predict these interactions from sequence data. In this work, we used a large quantitative set of 4,549 bZIP coiled-coil interactions to develop a predictive model that exploits knowledge of structurally conserved residue-residue interactions in the coiled-coil motif. Our model, which expresses interaction energies as a sum of interpretable residue-pair and triplet terms, achieves a correlation with experimental binding free energies of R = 0.68 and significantly out-performs other scoring functions. To use our model in protein design applications, we devised a strategy in which synthetic peptides are built by assembling 7-residue native-protein heptad modules into new combinations. An integer linear program was used to find the optimal combination of heptads to bind selectively to a target human bZIP coiled coil, but not to target paralogs. Using this approach, we designed peptides to interact with the bZIP domains from human JUN, XBP1, ATF4 and ATF5. Testing more than 132 candidate protein complexes using a fluorescence resonance energy transfer assay confirmed the formation of tight and selective heterodimers between the designed peptides and their targets. This approach can be used to make inhibitors of native proteins, or to develop novel peptides for applications in synthetic biology or nanotechnology.
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spelling pubmed-43350622015-02-24 Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions Potapov, Vladimir Kaplan, Jenifer B. Keating, Amy E. PLoS Comput Biol Research Article Selective dimerization of the basic-region leucine-zipper (bZIP) transcription factors presents a vivid example of how a high degree of interaction specificity can be achieved within a family of structurally similar proteins. The coiled-coil motif that mediates homo- or hetero-dimerization of the bZIP proteins has been intensively studied, and a variety of methods have been proposed to predict these interactions from sequence data. In this work, we used a large quantitative set of 4,549 bZIP coiled-coil interactions to develop a predictive model that exploits knowledge of structurally conserved residue-residue interactions in the coiled-coil motif. Our model, which expresses interaction energies as a sum of interpretable residue-pair and triplet terms, achieves a correlation with experimental binding free energies of R = 0.68 and significantly out-performs other scoring functions. To use our model in protein design applications, we devised a strategy in which synthetic peptides are built by assembling 7-residue native-protein heptad modules into new combinations. An integer linear program was used to find the optimal combination of heptads to bind selectively to a target human bZIP coiled coil, but not to target paralogs. Using this approach, we designed peptides to interact with the bZIP domains from human JUN, XBP1, ATF4 and ATF5. Testing more than 132 candidate protein complexes using a fluorescence resonance energy transfer assay confirmed the formation of tight and selective heterodimers between the designed peptides and their targets. This approach can be used to make inhibitors of native proteins, or to develop novel peptides for applications in synthetic biology or nanotechnology. Public Library of Science 2015-02-19 /pmc/articles/PMC4335062/ /pubmed/25695764 http://dx.doi.org/10.1371/journal.pcbi.1004046 Text en © 2015 Potapov et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Potapov, Vladimir
Kaplan, Jenifer B.
Keating, Amy E.
Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title_full Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title_fullStr Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title_full_unstemmed Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title_short Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions
title_sort data-driven prediction and design of bzip coiled-coil interactions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335062/
https://www.ncbi.nlm.nih.gov/pubmed/25695764
http://dx.doi.org/10.1371/journal.pcbi.1004046
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