PNAS, vol. 114 no. 21
Adela M. Candel, E4122–E4123.
doi: 10.1073/pnas.1703227114
Fast folding and slow unfolding of a resurrected Precambrian protein
Fast folding and slow unfolding of a resurrected Precambrian protein
Adela M. Candel a, M. Luisa Romero-Romero a,1, Gloria Gamiz-Arco a, Beatriz Ibarra-Molero a, and Jose M. Sanchez-Ruiz a,2
Author Affiliations
a Departamento de Quimica Fisica, Facultad de Ciencias, Universidad de Granada, Granada 18071, Spain
Source/Fonte: MD Simulation of Protein Folding
Tzul et al. (1) report different unfolding rates and similar folding rates for a number of thioredoxins. The authors interpret this result as evidence of the principle of minimal frustration. Their study includes several resurrected Precambrian thioredoxins that we have previously prepared and characterized (2⇓⇓–5).
We agree that the principle of minimal frustration is essential to understand protein evolution. However, approximate folding-rate invariance is easily explained without invoking this principle. Thioredoxin kinetic stability relies on a transition state that is substantially unstructured (5, 6). Therefore, mutations that changed unfolding rates to tune kinetic stability during evolution likely had much less effect on folding rates, as implied by the well-known principles of ϕ-value analysis (7).
Moreover, our experimental results are not consistent with folding-rate invariance being a general feature of thioredoxins. Fig. 1 shows folding–unfolding rates for the modern Escherichia coli thioredoxin and a resurrected Precambrian thioredoxin. The unfolding of the ancestral protein is ∼three orders-of-magnitude slower than the unfolding of the modern protein, indicating enhanced kinetic stability. However, in clear …
↵2To whom correspondence should be addressed. Email: sanchezr@ugr.es.
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