Evolution of Fold-Switching in a Metamorphic Protein
By Acacia F. Dishman, Robert C Tyler, Jamie C. Fox, A. Kleist, K. Prehoda, M. M. Babu, F. Peterson, B. Volkman. 2020
96 citations recorded by the source corpus.
One sequence encoding two structures Most proteins have stable, folded structures, but there are rare examples of metamorphic proteins that can switch between two different folds that may each have a different function. Dishman et al. investigated the evolution of XCL1, which is a member of the chemokine family that interconverts between the chemokine fold and a second, noncanonical fold that forms dimers. The authors used nuclear magnetic resonance spectroscopy to investigate the structures of inferred evolutionary ancestral sequences. Their results suggest that XCL1 evolved from an ancestor with the chemokine fold and then transitioned to prefer the noncanonical fold before reaching the modern-day metamorphic protein. Science, this issue p. 86 The human protein XCL1 evolved to switch between two completely different folds with different functions. Metamorphic proteins switch between different folds, defying the protein folding paradigm. It is unclear how fold switching arises during evolution. With ancestral reconstruction and nuclear magnetic resonance, we studied the evolution of the metamorphic human protein XCL1, which has two distinct folds with different functions, making it an unusual member of the chemokine family, whose members generally adopt one conserved fold. XCL1 evolved from an ancestor with the chemokine fold. Evolution of a dimer interface, changes in structural constraints and molecular strain, and alteration of intramolecular protein contacts drove the evolution of metamorphosis. Then, XCL1 likely evolved to preferentially populate the noncanonical fold before reaching its modern-day near-equal population of folds. These discoveries illuminate how one sequence has evolved to encode multiple structures, revealing principles for protein design and engineering.
Subfields: Molecular Biology
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In Molecular Biology
- Lucy J. Colwell
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Citations in the corpus
- Predicting multiple conformations via sequence clustering and AlphaFold2 (2023, neutral): “This is consistent with findings for the fold-switching proteins RfaH 45 and lymphotac-tin 46 , as well as non-fold-switching proteins such as the Cro repressor family 47 .”
- AlphaFold2 fails to predict protein fold switching (2022, background): “Furthermore, detailed biophysical characterization of fold-switching proteins 45,46 is needed.”
- Prediction of multiple conformational states by combining sequence clustering with AlphaFold2 (2022, background): “It would not be surprising that the KaiB family would contain pockets of constructs that are stabilized for one or the other, as has been found for the fold-switchers RfaH 44 and lymphotactin 45 , as well as non-fold-switching proteins like the Cro repressor family 46 .”