Main content area

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.