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Rapid determination of quaternary protein structures in complex biological samples


Hauri, Simon; Khakzad, Hamed; Happonen, Lotta; Teleman, Johan; Malmström, Johan; Malmström, Lars (2019). Rapid determination of quaternary protein structures in complex biological samples. Nature Communications, 10(1):192.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute for Computational Science
Dewey Decimal Classification:530 Physics
Scopus Subject Areas:Physical Sciences > General Chemistry
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Physical Sciences > General Physics and Astronomy
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry
Language:English
Date:1 December 2019
Deposited On:12 Feb 2019 09:25
Last Modified:15 Apr 2020 23:21
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-018-07986-1

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