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Rapid determination of quaternary protein structures in complex biological samples

Hauri, Simon LU ; Khakzad, Hamed ; Happonen, Lotta LU ; Teleman, Johan LU ; Malmström, Johan LU and Malmström, Lars LU (2019) In Nature Communications 10.
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
10
article number
192
publisher
Nature Publishing Group
external identifiers
  • scopus:85060008705
  • pmid:30643114
ISSN
2041-1723
DOI
10.1038/s41467-018-07986-1
language
English
LU publication?
yes
id
4093fc55-4615-4bc1-8c44-503a0e6c30bc
date added to LUP
2019-01-22 10:51:56
date last changed
2020-10-20 01:31:49
@article{4093fc55-4615-4bc1-8c44-503a0e6c30bc,
  abstract     = {<p>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.</p>},
  author       = {Hauri, Simon and Khakzad, Hamed and Happonen, Lotta and Teleman, Johan and Malmström, Johan and Malmström, Lars},
  issn         = {2041-1723},
  language     = {eng},
  month        = {01},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Rapid determination of quaternary protein structures in complex biological samples},
  url          = {http://dx.doi.org/10.1038/s41467-018-07986-1},
  doi          = {10.1038/s41467-018-07986-1},
  volume       = {10},
  year         = {2019},
}