Stability Effect of Quinary Interactions Reversed by Single Point Mutations

David Gnutt, Stepan Timr, Jonas Ahlers, Benedikt König, Emily Manderfeld, Matthias Heyden, Fabio Sterpone, Simon Ebbinghaus

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4660-4669
Number of pages10
JournalJournal of the American Chemical Society
Volume141
Issue number11
DOIs
StatePublished - Mar 20 2019

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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