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Designed allosteric protein logic

Tjaša Plaper, Estera Merljak, Tina Fink, Duško Lainšček, Tadej Satler, Vid Jazbec, Mojca Benčina, View ORCID ProfileRoman Jerala
doi: https://doi.org/10.1101/2022.06.03.494683
Tjaša Plaper
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
2Interdisciplinary doctoral study of biomedicine, Medical faculty, University of Ljubljana,1000 Ljubljana, Slovenia
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Estera Merljak
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
2Interdisciplinary doctoral study of biomedicine, Medical faculty, University of Ljubljana,1000 Ljubljana, Slovenia
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Tina Fink
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
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Duško Lainšček
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
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Tadej Satler
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
2Interdisciplinary doctoral study of biomedicine, Medical faculty, University of Ljubljana,1000 Ljubljana, Slovenia
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Vid Jazbec
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
2Interdisciplinary doctoral study of biomedicine, Medical faculty, University of Ljubljana,1000 Ljubljana, Slovenia
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Mojca Benčina
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
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Roman Jerala
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
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  • ORCID record for Roman Jerala
  • For correspondence: roman.jerala@ki.si
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SUMMARY

Regulation of the activity of proteins enables control of complex cellular processes. Allosteric regulation has been introduced individually into few natural proteins. Here, we present a generally applicable regulation of diverse proteins called INSRTR (inserted peptide structure regulator), based on inserting a short unstructured peptide into a solvent-accessible loop that retains protein function. Function of the target protein can be inactivated by the addition of a peptide that forms a rigid coiled-coil dimer. This platform enables the construction of ON/OFF protein switches, their regulation by small molecules, and Boolean logic functions with a rapid response in mammalian cells. INSRTR can be used to regulate a wide range of proteins, as demonstrated on ten members of protein families with diverse biological activities including enzymes, signaling mediators, DNA binders/transcriptional regulators, fluorescent protein, and antibodies regulating chimeric antigen receptor. INSRTR platform presents an extraordinary potential for regulating biological systems and applications.

One sentence summary Authors have designed a widely applicable system to activate or inactivate function of diverse proteins or form Boolean logic gates based on formation of a coiled-coil dimer within protein loops and demonstrated its implementation on a range of 10 diverse proteins.

Competing Interest Statement

Patent application on INSRTR has been filed by the authors of the paper.

Footnotes

  • ↵# Lead contact

Copyright 
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 June 03, 2022.
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Designed allosteric protein logic
Tjaša Plaper, Estera Merljak, Tina Fink, Duško Lainšček, Tadej Satler, Vid Jazbec, Mojca Benčina, Roman Jerala
bioRxiv 2022.06.03.494683; doi: https://doi.org/10.1101/2022.06.03.494683
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Designed allosteric protein logic
Tjaša Plaper, Estera Merljak, Tina Fink, Duško Lainšček, Tadej Satler, Vid Jazbec, Mojca Benčina, Roman Jerala
bioRxiv 2022.06.03.494683; doi: https://doi.org/10.1101/2022.06.03.494683

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