Rapid determination of quaternary protein structures in complex biological samples

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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.

In: Nature Communications, Vol. 10, 192, 14.01.2019.

Research output: Contribution to journalArticle

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TY - JOUR

T1 - Rapid determination of quaternary protein structures in complex biological samples

AU - Hauri, Simon

AU - Khakzad, Hamed

AU - Happonen, Lotta

AU - Teleman, Johan

AU - Malmström, Johan

AU - Malmström, Lars

PY - 2019/1/14

Y1 - 2019/1/14

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-07986-1

DO - 10.1038/s41467-018-07986-1

M3 - Article

VL - 10

JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 192

ER -