TY - JOUR
T1 - Stability Effect of Quinary Interactions Reversed by Single Point Mutations
AU - Gnutt, David
AU - Timr, Stepan
AU - Ahlers, Jonas
AU - König, Benedikt
AU - Manderfeld, Emily
AU - Heyden, Matthias
AU - Sterpone, Fabio
AU - Ebbinghaus, Simon
N1 - Funding Information:
S.E. and D.G. acknowledge funding from the Cluster of Excellence RESOLV (EXC 1069), the Human Frontier Science Program (RGP0022/2017), the German-Israeli Foundation for Scientific Research and Development (grant 1410), and the International Graduate School of Neuroscience (Ruhr-University Bochum). The research leading to these results has further received funding from the ERC (FP7/2007-2013) Grant Agreement no. 258748 (F.S.). Part of this work was performed using HPC resources from GENCI [CINES, TGCC, IDRIS] (Grant x20186818). F.S. and S.T. acknowledge the financial support by the “Initiative d’Excellence” program from the French State (Grant “DYNAMO”, ANR-11-LABX-0011-01). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE programme coordinated by Campus France (S.T.). S.T. also acknowledges the Rothschild Foundation for fellowship support. We thank J. Schnatwinkel for experimental help and M. Oliveberg and J. Danielsson for providing the SOD1bar plasmid and helpful discussions.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/3/20
Y1 - 2019/3/20
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.8b13025
DO - 10.1021/jacs.8b13025
M3 - Article
C2 - 30740972
AN - SCOPUS:85062350445
SN - 0002-7863
VL - 141
SP - 4660
EP - 4669
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 11
ER -