Validated determination of NRG1 Ig-like domain structure by mass spectrometry coupled with computational modeling
Niloofar Abolhasani Khaje, Alexander Eletsky, Sarah E. Biehn, Charles K. Mobley, Monique J. Rogals, Yoonkyoo Kim, Sushil K. Mishra, Robert J. Doerksen, Steffen Lindert, James H. Prestegard, Joshua S. Sharp
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Source: Crossref
Published: May 12, 2022
DOI: 10.1038/s42003-022-03411-y
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Abstract High resolution hydroxyl radical protein footprinting (HR-HRPF) is a mass spectrometry-based method that measures the solvent exposure of multiple amino acids in a single experiment, offering constraints for experimentally informed computational modeling. HR-HRPF-based modeling has previously been used to accurately model the structure of proteins of known structure, but the technique has never been used to determine the structure of a protein of unknown structure. Here, we present the use of HR-HRPF-based modeling to determine the structure of the Ig-like domain of NRG1, a protein with no close homolog of known structure. Independent determination of the protein structure by both HR-HRPF-based modeling and heteronuclear NMR was carried out, with results compared only after both processes were complete. The HR-HRPF-based model was highly similar to the lowest energy NMR model, with a backbone RMSD of 1.6 Å. To our knowledge, this is the first use of HR-HRPF-based modeling to determine a previously uncharacterized protein structure.
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