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Journal Articles Nature Year : 2022

Visualizing protein breathing motions associated with aromatic ring flipping


Aromatic residues cluster in the core of folded proteins, where they stabilize the structure through multiple interactions. Nuclear magnetic resonance (NMR) studies in the 1970s showed that aromatic side chains can undergo ring flips-that is, 180° rotations-despite their role in maintaining the protein fold1-3. It was suggested that large-scale 'breathing' motions of the surrounding protein environment would be necessary to accommodate these ring flipping events1. However, the structural details of these motions have remained unclear. Here we uncover the structural rearrangements that accompany ring flipping of a buried tyrosine residue in an SH3 domain. Using NMR, we show that the tyrosine side chain flips to a low-populated, minor state and, through a proteome-wide sequence analysis, we design mutants that stabilize this state, which allows us to capture its high-resolution structure by X-ray crystallography. A void volume is generated around the tyrosine ring during the structural transition between the major and minor state, and this allows fast flipping to take place. Our results provide structural insights into the protein breathing motions that are associated with ring flipping. More generally, our study has implications for protein design and structure prediction by showing how the local protein environment influences amino acid side chain conformations and vice versa.
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Origin : Publication funded by an institution

Dates and versions

hal-03582487 , version 1 (21-02-2022)



Laura Mariño Pérez, Francesco S Ielasi, Luiza M Bessa, Damien Maurin, Jaka Kragelj, et al.. Visualizing protein breathing motions associated with aromatic ring flipping. Nature, 2022, ⟨10.1038/s41586-022-04417-6⟩. ⟨hal-03582487⟩
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