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MaXLinker: proteome-wide cross-link identifications with high specificity and sensitivity

Kumar Yugandhar, Ting-Yi Wang, Alden King-Yung Leung, Michael Charles Lanz, Ievgen Motorykin, Jin Liang, Elnur Elyar Shayhidin, Marcus Bustamante Smolka, Sheng Zhang, Haiyuan Yu
doi: https://doi.org/10.1101/526897
Kumar Yugandhar
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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Ting-Yi Wang
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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Alden King-Yung Leung
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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Michael Charles Lanz
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
3Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
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Ievgen Motorykin
4Mass Spectrometry and Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York,14853, USA
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Jin Liang
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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Elnur Elyar Shayhidin
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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Marcus Bustamante Smolka
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
3Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
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Sheng Zhang
4Mass Spectrometry and Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, New York,14853, USA
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Haiyuan Yu
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York,14853, USA
2Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853, USA
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  • For correspondence: haiyuan.yu@cornell.edu
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ABSTRACT

Protein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. However, the current cross-link search algorithms follow an “MS2-centric” approach and, as a result, suffer from a high rate of mis-identified cross-links (~15%). We address this urgent problem, by designing a novel “MS3-centric” approach for cross-link identification and implemented it as a search engine called MaXLinker. MaXLinker significantly outperforms the current state of the art search engine with up to 18-fold lower false positive rate. Additionally, MaXLinker results in up to 31% more cross-links, demonstrating its superior sensitivity and specificity. Moreover, we performed proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we unveiled the most comprehensive set of 9,319 unique cross-links at 1% false discovery rate, comprising 8,051 intraprotein and 1,268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinker’s robust performance.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2019.
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MaXLinker: proteome-wide cross-link identifications with high specificity and sensitivity
Kumar Yugandhar, Ting-Yi Wang, Alden King-Yung Leung, Michael Charles Lanz, Ievgen Motorykin, Jin Liang, Elnur Elyar Shayhidin, Marcus Bustamante Smolka, Sheng Zhang, Haiyuan Yu
bioRxiv 526897; doi: https://doi.org/10.1101/526897
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MaXLinker: proteome-wide cross-link identifications with high specificity and sensitivity
Kumar Yugandhar, Ting-Yi Wang, Alden King-Yung Leung, Michael Charles Lanz, Ievgen Motorykin, Jin Liang, Elnur Elyar Shayhidin, Marcus Bustamante Smolka, Sheng Zhang, Haiyuan Yu
bioRxiv 526897; doi: https://doi.org/10.1101/526897

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