Chemical cross-linking and mass spectrometry are used to reveal how a single protein folds differently to form distinct prion strains. Intra- and intermolecular cross-linking are distinguished by MS/MS on the VK and VL strains seeded from equally mixed 14N- and 15N-labeled Sup35 protein. Amino acid residue adjacencies revealed by cross-linking are used to constrain different Sup35 chain folds.
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