Mutational tipping points for switching protein folds and functions

By Yanan He, Yihong Chen, P. Alexander, P. Bryan, J. Orban. 2012

112 citations recorded by the source corpus.

SUMMARY While disordered to ordered rearrangements are relatively common, the ability of proteins to switch from one ordered fold to a completely different fold is generally regarded as rare and few fold switches have been characterized. Here, in a designed system, we examine the mutational requirements for transitioning between folds and functions. We show that switching between monomeric 3α and 4β+α folds can occur in multiple ways with successive single amino acid changes at diverse residue positions, raising the likelihood that such transitions occur in the evolution of new folds. Even mutations on the periphery of the core can tip the balance between alternatively folded states. Ligand-binding studies illustrate that a new IgG-binding function can be gained well before the relevant 4β+α fold is appreciably populated in the unbound protein. The results provide new insights into the evolution of fold and function.

Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging

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In Molecular Biology

Citations in the corpus

Predicting multiple conformations via sequence clustering and AlphaFold2 (2023, positive): “Starting from two naturally occurring 56-amino-acid domains from the multidomain protein G, in which G A adopts a 3-α-helix and G B a 4b+a fold, variants had been engineered to switch between both folds 49–51 (Extended Data Fig.”