Open AccessMutant libraries reveal negative design shielding proteins from supramolecular self-assembly and relocalization in cells
Author(s) -
Hector GarciaSeisdedos,
Tal Levin,
Gal Shapira,
Saskia Freud,
Emmanuel D. Levy
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2101117119
Subject(s) - mutant , phenotype , mutation , context (archaeology) , biology , protein structure , genetics , alanine scanning , microbiology and biotechnology , biophysics , gene , biochemistry , mutagenesis , paleontology
Significance Genetic mutations fuel organismal evolution but can also cause disease. As proteins are the cell’s workhorses, the ways in which mutations can disrupt their structure, stability, function, and interactions have been studied extensively. However, proteins evolve and function in a cellular context, and our ability to relate changes in protein sequence to cell-level phenotypes remains limited. In particular, the molecular mechanism underlying most disease-associated mutations is unknown. Here, we show that mutations changing a protein’s surface chemistry can dramatically impact its supramolecular self-assembly and localization in the cell. These results highlight the complex nature of genotype–phenotype relationships with a simple system.