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Stability Effect of Quinary Interactions Reversed by Single Point Mutations
- Gnutt, David, Timr, Stepan, Ahlers, Jonas, König, Benedikt, Manderfeld, Emily, Heyden, Matthias, Sterpone, Fabio, Ebbinghaus, Simon
- Journal of the American Chemical Society 2019 v.141 no.11 pp. 4660-4669
- amino acids, mammals, mutants, mutational analysis, point mutation, protein folding, proteins, structural biology, superoxide dismutase
- In cells, proteins are embedded in a crowded environment that controls their properties via manifold avenues including weak protein–macromolecule interactions. A molecular level understanding of these quinary interactions and their contribution to protein stability, function, and localization in the cell is central to modern structural biology. Using a mutational analysis to quantify the energetic contributions of single amino acids to the stability of the ALS related protein superoxide dismutase I (SOD1) in mammalian cells, we show that quinary interactions destabilize SOD1 by a similar energetic offset for most of the mutants, but there are notable exceptions: Mutants that alter its surface properties can even lead to a stabilization of the protein in the cell as compared to the test tube. In conclusion, quinary interactions can amplify and even reverse the mutational response of proteins, being a key aspect in pathogenic protein misfolding and aggregation.