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Publication Abstract from PubMed

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 degrees rotations-despite their role in maintaining the protein fold(1-3). It was suggested that large-scale 'breathing' motions of the surrounding protein environment would be necessary to accommodate these ring flipping events(1). 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.

Visualizing protein breathing motions associated with aromatic ring flipping.,Marino Perez L, Ielasi FS, Bessa LM, Maurin D, Kragelj J, Blackledge M, Salvi N, Bouvignies G, Palencia A, Jensen MR Nature. 2022 Feb;602(7898):695-700. doi: 10.1038/s41586-022-04417-6. Epub 2022, Feb 16. PMID:35173330^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.