Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 19, Pages 7684-7689Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1305887110
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Funding
- National Institutes of Health [RO1 GM031847, R01 GM 50945, GM0827, GM008295]
- National Science Foundation [MCB1020649]
- Mathers Charitable Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1051344] Funding Source: National Science Foundation
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The kinetic folding of ribonuclease H was studied by hydrogen exchange (HX) pulse labeling with analysis by an advanced fragment separation mass spectrometry technology. The results show that folding proceeds through distinct intermediates in a stepwise pathway that sequentially incorporates cooperative native-like structural elements to build the native protein. Each step is seen as a concerted transition of one or more segments from an HX-unprotected to an HX-protected state. Deconvolution of the data to near amino acid resolution shows that each step corresponds to the folding of a secondary structural element of the native protein, termed a foldon. Each folded segment is retained through subsequent steps of foldon addition, revealing a stepwise buildup of the native structure via a single dominant pathway. Analysis of the pertinent literature suggests that this model is consistent with experimental results for many proteins and some current theoretical results. Two biophysical principles appear to dictate this behavior. The principle of cooperativity determines the central role of native-like foldon units. An interaction principle termed sequential stabilization based on native-like interfoldon interactions orders the pathway.
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