Influence of denatured and intermediate states of folding on protein aggregation
| Autor: | Scott A. Brown, Teresa Head-Gordon, Victor Chubukov, Nicolas L. Fawzi, Louis A. Clark |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Protein Denaturation Protein Folding biology Chemistry Proteins Phi value analysis Protein aggregation Contact order Biochemistry Article Kinetics Crystallography Protein L Bacterial Proteins Lattice protein biology.protein Biophysics Thermodynamics Denaturation (biochemistry) Protein folding Protein G Molecular Biology |
| Zdroj: | Protein Science. 14:993-1003 |
| ISSN: | 1469-896X 0961-8368 |
| Popis: | We simulate the aggregation thermodynamics and kinetics of proteins L and G, each of which self-assembles to the same alpha/beta [corrected] topology through distinct folding mechanisms. We find that the aggregation kinetics of both proteins at an experimentally relevant concentration exhibit both fast and slow aggregation pathways, although a greater proportion of protein G aggregation events are slow relative to those of found for protein L. These kinetic differences are correlated with the amount and distribution of intrachain contacts formed in the denatured state ensemble (DSE), or an intermediate state ensemble (ISE) if it exists, as well as the folding timescales of the two proteins. Protein G aggregates more slowly than protein L due to its rapidly formed folding intermediate, which exhibits native intrachain contacts spread across the protein, suggesting that certain early folding intermediates may be selected for by evolution due to their protective role against unwanted aggregation. Protein L shows only localized native structure in the DSE with timescales of folding that are commensurate with the aggregation timescale, leaving it vulnerable to domain swapping or nonnative interactions with other chains that increase the aggregation rate. Folding experiments that characterize the structural signatures of the DSE, ISE, or the transition state ensemble (TSE) under nonaggregating conditions should be able to predict regions where interchain contacts will be made in the aggregate, and to predict slower aggregation rates for proteins with contacts that are dispersed across the fold. Since proteins L and G can both form amyloid fibrils, this work also provides mechanistic and structural insight into the formation of prefibrillar species. |
| Databáze: | OpenAIRE |
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