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Rapid determination of quaternary protein structures in complex biological samples

Author

Listed:
  • Simon Hauri

    (Lund University)

  • Hamed Khakzad

    (S3IT, University of Zurich
    University of Zurich)

  • Lotta Happonen

    (Lund University)

  • Johan Teleman

    (Lund University)

  • Johan Malmström

    (Lund University)

  • Lars Malmström

    (Lund University
    S3IT, University of Zurich
    University of Zurich)

Abstract

The understanding of complex biological systems is still hampered by limited knowledge of biologically relevant quaternary protein structures. Here, we demonstrate quaternary structure determination in biological samples using a combination of chemical cross-linking, high-resolution mass spectrometry and high-accuracy protein structure modeling. This approach, termed targeted cross-linking mass spectrometry (TX-MS), relies on computational structural models to score sets of targeted cross-linked peptide signals acquired using a combination of mass spectrometry acquisition techniques. We demonstrate the utility of TX-MS by creating a high-resolution quaternary model of a 1.8 MDa protein complex composed of a pathogen surface protein and ten human plasma proteins. The model is based on a dense network of cross-link distance constraints obtained directly in a mixture of human plasma and live bacteria. These results demonstrate that TX-MS can increase the applicability of flexible backbone docking algorithms to large protein complexes by providing rich cross-link distance information from complex biological samples.

Suggested Citation

  • Simon Hauri & Hamed Khakzad & Lotta Happonen & Johan Teleman & Johan Malmström & Lars Malmström, 2019. "Rapid determination of quaternary protein structures in complex biological samples," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07986-1
    DOI: 10.1038/s41467-018-07986-1
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    Cited by:

    1. Arman Izadi & Yasaman Karami & Eleni Bratanis & Sebastian Wrighton & Hamed Khakzad & Maria Nyblom & Berit Olofsson & Lotta Happonen & Di Tang & Martin Sundwall & Magdalena Godzwon & Yashuan Chao & Ale, 2024. "The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. SM Bargeen Alam Turzo & Justin T. Seffernick & Amber D. Rolland & Micah T. Donor & Sten Heinze & James S. Prell & Vicki H. Wysocki & Steffen Lindert, 2022. "Protein shape sampled by ion mobility mass spectrometry consistently improves protein structure prediction," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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