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

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 () and Ying Ge ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43321-z

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