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Reversible switching between two common protein folds in a designed system using only temperature



Tsega Solomon, Yanan He, Fahriye Nese Sari, Yihong Chen, David Travis Gallagher, Philip Bryan, John Orban


Naturally occurring metamorphic proteins have the ability to interconvert from one folded state to another through either a limited set of mutations or by way of a change in the local environment. Here, we show that it is possible to switch reversibly between two of the most common folds employing only temperature changes in a designed system. We demonstrate that a latent 3-alpha state can be unmasked from an alpha/beta-plait topology with a single V90T amino acid substitution, populating both forms simultaneously. The equilibrium between these two states exhibits temperature dependence, such that the 3-alpha state is predominant (>90%) at 5oC, while the alpha/beta-plait fold is the major species (>90%) at 30oC. We describe the structure and dynamics of these topologies, how mutational changes affect the temperature dependence, and the energetics and kinetics of inter-conversion. Additionally, we demonstrate how ligand binding function can be tightly regulated by large amplitude changes in protein structure over a relatively narrow temperature range. This fold switch thus represents a potentially useful approach for designing proteins that alter their fold topologies in response to environmental triggers. It may also serve as a model for computational studies of temperature dependent protein stability and fold switching. To the best of our knowledge, this is the first description of switching between two distinct monomeric protein folds using only temperature in either a designed or natural system.
Proceedings of the National Academy of Sciences


protein fold switching, metamorphic proteins, protein design, NMR, protein structure, dynamics, energetics, environmental triggering, fold evolution, functional regulation


Solomon, T. , He, Y. , Sari, F. , Chen, Y. , Gallagher, D. , Bryan, P. and Orban, J. (2023), Reversible switching between two common protein folds in a designed system using only temperature, Proceedings of the National Academy of Sciences, [online],, (Accessed June 21, 2024)


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Created January 19, 2023, Updated March 13, 2023