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Extreme disorder in an ultrahigh-affinity protein complex

Author

Listed:
  • Alessandro Borgia

    (University of Zurich)

  • Madeleine B. Borgia

    (University of Zurich)

  • Katrine Bugge

    (Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen)

  • Vera M. Kissling

    (University of Zurich)

  • Pétur O. Heidarsson

    (University of Zurich)

  • Catarina B. Fernandes

    (Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen)

  • Andrea Sottini

    (University of Zurich)

  • Andrea Soranno

    (University of Zurich
    Washington University School of Medicine)

  • Karin J. Buholzer

    (University of Zurich)

  • Daniel Nettels

    (University of Zurich)

  • Birthe B. Kragelund

    (Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), University of Copenhagen)

  • Robert B. Best

    (Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Benjamin Schuler

    (University of Zurich
    University of Zurich)

Abstract

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

Suggested Citation

  • Alessandro Borgia & Madeleine B. Borgia & Katrine Bugge & Vera M. Kissling & Pétur O. Heidarsson & Catarina B. Fernandes & Andrea Sottini & Andrea Soranno & Karin J. Buholzer & Daniel Nettels & Birthe, 2018. "Extreme disorder in an ultrahigh-affinity protein complex," Nature, Nature, vol. 555(7694), pages 61-66, March.
  • Handle: RePEc:nat:nature:v:555:y:2018:i:7694:d:10.1038_nature25762
    DOI: 10.1038/nature25762
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    Citations

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    Cited by:

    1. Wenzhe Liu & Limin Chen & Dongbao Yin & Zhiheng Yang & Jianfei Feng & Qi Sun & Luhua Lai & Xuefeng Guo, 2023. "Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Sveinn Bjarnason & Jordan A. P. McIvor & Andreas Prestel & Kinga S. Demény & Jakob T. Bullerjahn & Birthe B. Kragelund & Davide Mercadante & Pétur O. Heidarsson, 2024. "DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Andrea E Rawlings & Panah Liravi & Sybilla Corbett & Alex S Holehouse & Sarah S Staniland, 2020. "Investigating the ferric ion binding site of magnetite biomineralisation protein Mms6," PLOS ONE, Public Library of Science, vol. 15(2), pages 1-16, February.
    4. Ricardo Celestino & Morkos A Henen & José B Gama & Cátia Carvalho & Maxwell McCabe & Daniel J Barbosa & Alexandra Born & Parker J Nichols & Ana X Carvalho & Reto Gassmann & Beat Vögeli, 2019. "A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport," PLOS Biology, Public Library of Science, vol. 17(1), pages 1-33, January.
    5. Malisa Vittoria Mantonico & Federica Leo & Giacomo Quilici & Liam Sean Colley & Francesco Marchis & Massimo Crippa & Rosanna Mezzapelle & Tim Schulte & Chiara Zucchelli & Chiara Pastorello & Camilla C, 2024. "The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Meaghan S. Jankowski & Daniel Griffith & Divya G. Shastry & Jacqueline F. Pelham & Garrett M. Ginell & Joshua Thomas & Pankaj Karande & Alex S. Holehouse & Jennifer M. Hurley, 2024. "Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Anna C. Papageorgiou & Michaela Pospisilova & Jakub Cibulka & Raghib Ashraf & Christopher A. Waudby & Pavel Kadeřávek & Volha Maroz & Karel Kubicek & Zbynek Prokop & Lumir Krejci & Konstantinos Tripsi, 2023. "Recognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Bikash Chandra Swain & Pascale Sarkis & Vanessa Ung & Sabrina Rousseau & Laurent Fernandez & Ani Meltonyan & V. Esperance Aho & Davide Mercadante & Cameron D. Mackereth & Mikayel Aznauryan, 2024. "Disordered regions of human eIF4B orchestrate a dynamic self-association landscape," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    9. San Hadži & Zala Živič & Matic Kovačič & Uroš Zavrtanik & Sarah Haesaerts & Daniel Charlier & Janez Plavec & Alexander N. Volkov & Jurij Lah & Remy Loris, 2024. "Fuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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