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Structure. 2017 Dec 5;25(12):1867-1874.e3. doi: 10.1016/j.str.2017.11.002.

Promiscuous Protein Binding as a Function of Protein Stability.

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Department of Biomolecular Sciences, Weizmann Institute of Science, 76100 Rehovot, Israel.
Structural Proteomic Unit, Weizmann Institute of Science, 76100 Rehovot, Israel.
Department of Biomolecular Sciences, Weizmann Institute of Science, 76100 Rehovot, Israel. Electronic address:


Proteins have evolved to balance efficient binding of desired partners with rejection of unwanted interactions. To investigate the evolution of protein-protein interactions, we selected a random library of pre-stabilized TEM1 β-lactamase against wild-type TEM1 using yeast surface display. Three mutations were sufficient to achieve micromolar affinity binding between the two. The X-ray structure emphasized that the main contribution of the selected mutations was to modify the protein fold, specifically removing the N'-terminal helix, which consequently allowed protein coupling via a β-sheet-mediated interaction resembling amyloid interaction mode. The only selected mutation located at the interaction interface (E58V) is reminiscent of the single mutation commonly causing sickle-cell anemia. Interestingly, the evolved mutations cannot be inserted into the wild-type protein due to reduced thermal stability of the resulting mutant protein. These results reveal a simple mechanism by which undesirable binding is purged by loss of thermal stability.


TEM1; de novo protein interaction; dimerization; evolution; mutations; promiscuity; protein-protein; specificity; thermal stability; β-sheet augmentation

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