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Design and characterization of a protein fold switching network



David Travis Gallagher, Biao Ruan, Yanan He, Yingwei Chen, Eun Jung Choi, Yihong Chen, Dana Motabar, Tsega Solomon, Richard Simmerman, Thomas Kauffman, John Orban, Philip Bryan


Protein sequences encoding three common small folds (3-alpha, beta-grasp, and alpha/beta plait) were connected in a network of mutational pathways that intersect at high-identity sequences, termed nodes. The structures of proteins around nodes were determined using NMR spectroscopy and analyzed for stability and binding function. To generate nodes, the amino acid sequence encoding a shorter fold (3-alpha or beta-grasp) is embedded in the structure of the 50% longer alpha/beta plait fold and a new sequence is designed that satisfies two sets of native interactions. This leads to protein pairs with a 3-alpha or beta-grasp fold in the shorter form but an alpha-beta plait fold in the longer form. Further, embedding smaller antagonistic folds in longer folds creates critical states in the longer folds such that single amino acid substitutions can switch both their fold and function. This suggests that abrupt fold switching may be a mechanism of evolving new protein structures and functions
Nature Communications


protein fold switching, metamorphic, design, NMR structure, evolution


Gallagher, D. , Ruan, B. , He, Y. , Chen, Y. , Choi, E. , Chen, Y. , Motabar, D. , Solomon, T. , Simmerman, R. , Kauffman, T. , Orban, J. and Bryan, P. (2023), Design and characterization of a protein fold switching network, Nature Communications, [online], (Accessed July 13, 2024)


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Created January 26, 2023, Updated August 29, 2023