Reverse hydrophobic effects relieved by amino-acid substitutions at a protein surface.
It is rare for amino-acid substitutions on the surface of proteins to have large stabilizing or destabilizing effects. Nevertheless, one substitution of this type, the Tyr 26----Cys mutation in lambda Cro, increases the melting temperature of the protein by 11 degrees C and the stability by 2.2 kcal mol-1. Here we show that the stability of Cro can be increased by many different amino-acid substitutions at position 26, with increasing stability showing a good correlation with decreasing side-chain hydrophobicity. As Tyr 26 is hyper-exposed to solvent in the Cro crystal structure, we suggest that wild-type and variant proteins with other hydrophobic side chains at position 26 are destabilized as a result of a reverse hydrophobic effect caused by the side chain being more exposed to solvent in the native than in the denatured state.
Pakula
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AA
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Sauer
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RT
D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D011487:Protein Conformation; D011489:Protein Denaturation; D012097:Repressor Proteins / Q000648:ultrastructure*; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014157:Transcription Factors / Q000648:ultrastructure*; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins