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A minimal sequence code for switching protein structure and function
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DOI：10.1073/pnas.0906408106.png)
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摘要
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We present here a structural and mechanistic description of how a protein changes its fold and function, mutation by mutation. Our approach was to create 2 proteins that (i) are stably folded into 2 different folds, (ii) have 2 different functions, and (iii) are very similar in sequence. In this simplified sequence space we explore the mutational path from one fold to another. We show that an IgG-binding, 4 beta + alpha fold can be transformed into an albumin-binding, 3-alpha fold via a mutational pathway in which neither function nor native structure is completely lost. The stabilities of all mutants along the pathway are evaluated, key high-resolution structures are determined by NMR, and an explanation of the switching mechanism is provided. We show that the conformational switch from 4 beta + alpha to 3-alpha structure can occur via a single amino acid substitution. On one side of the switch point, the 4 beta + alpha fold is >90% populated (pH 7.2, 20 degrees C). A single mutation switches the conformation to the 3-alpha fold, which is >90% populated (pH 7.2, 20 degrees C). We further show that a bifunctional protein exists at the switch point with affinity for both IgG and albumin.
Keyword:
evolution
NMR
protein design
protein folding
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9.1
论文数:
10.8W
被引数:
73.5W
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NMR structures of two designed proteins with high sequence identity but different fold and function
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