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Structure and dynamics of endogenous cardiac troponin complex in human heart tissue captured by native nanoproteomics

Author

Listed:
  • Emily A. Chapman

    (University of Wisconsin-Madison)

  • David S. Roberts

    (University of Wisconsin-Madison)

  • Timothy N. Tiambeng

    (University of Wisconsin-Madison)

  • Jãán Andrews

    (University of Wisconsin-Madison)

  • Man-Di Wang

    (University of Wisconsin-Madison)

  • Emily A. Reasoner

    (University of Wisconsin-Madison)

  • Jake A. Melby

    (University of Wisconsin-Madison)

  • Brad H. Li

    (University of Wisconsin-Madison)

  • Donguk Kim

    (University of Wisconsin-Madison)

  • Andrew J. Alpert

    (PolyLC Inc)

  • Song Jin

    (University of Wisconsin-Madison)

  • Ying Ge

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

Abstract

Protein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present challenges to study using conventional structural biology techniques. Here we develop a native nanoproteomics strategy for the enrichment and subsequent native top-down mass spectrometry (nTDMS) analysis of endogenous cardiac troponin (cTn) complex directly from human heart tissue. The cTn complex is enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complex, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the cTn complex, localizes Ca2+ binding domains, defines cTn-Ca2+ binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a paradigm for structural characterization of endogenous native protein complexes.

Suggested Citation

  • Emily A. Chapman & David S. Roberts & Timothy N. Tiambeng & Jãán Andrews & Man-Di Wang & Emily A. Reasoner & Jake A. Melby & Brad H. Li & Donguk Kim & Andrew J. Alpert & Song Jin & Ying Ge, 2023. "Structure and dynamics of endogenous cardiac troponin complex in human heart tissue captured by native nanoproteomics," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43321-z
    DOI: 10.1038/s41467-023-43321-z
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    References listed on IDEAS

    as
    1. Timothy N. Tiambeng & David S. Roberts & Kyle A. Brown & Yanlong Zhu & Bifan Chen & Zhijie Wu & Stanford D. Mitchell & Tania M. Guardado-Alvarez & Song Jin & Ying Ge, 2020. "Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. John C. Tran & Leonid Zamdborg & Dorothy R. Ahlf & Ji Eun Lee & Adam D. Catherman & Kenneth R. Durbin & Jeremiah D. Tipton & Adaikkalam Vellaichamy & John F. Kellie & Mingxi Li & Cong Wu & Steve M. M., 2011. "Mapping intact protein isoforms in discovery mode using top-down proteomics," Nature, Nature, vol. 480(7376), pages 254-258, December.
    3. Hsin-Yung Yen & Kin Kuan Hoi & Idlir Liko & George Hedger & Michael R. Horrell & Wanling Song & Di Wu & Philipp Heine & Tony Warne & Yang Lee & Byron Carpenter & Andreas Plückthun & Christopher G. Tat, 2018. "PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling," Nature, Nature, vol. 559(7714), pages 423-427, July.
    4. Soichi Takeda & Atsuko Yamashita & Kayo Maeda & Yuichiro Maéda, 2003. "Structure of the core domain of human cardiac troponin in the Ca2+-saturated form," Nature, Nature, vol. 424(6944), pages 35-41, July.
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