Structural coalescence underlies the aggregation propensity of a β-barrel protein motif.
A clear understanding of the structural foundations underlying protein aggregation is an elusive goal of central biomedical importance. A step toward this aim is exemplified by the β-barrel motif represented by the intestinal fatty acid binding protein (IFABP) and two abridged all-β sheet forms (Δ98...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
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| author | Carla R Angelani Julio J Caramelo Lucrecia M Curto José M Delfino |
| author_facet | Carla R Angelani Julio J Caramelo Lucrecia M Curto José M Delfino |
| author_sort | Carla R Angelani |
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| description | A clear understanding of the structural foundations underlying protein aggregation is an elusive goal of central biomedical importance. A step toward this aim is exemplified by the β-barrel motif represented by the intestinal fatty acid binding protein (IFABP) and two abridged all-β sheet forms (Δ98Δ and Δ78Δ). At odds with the established notion that a perturbation of the native fold should necessarily favor a buildup of intermediate forms with an enhanced tendency to aggregate, the intrinsic stability (ΔG°H2O) of these proteins does not bear a straightforward correlation with their trifluoroethanol (TFE)-induced aggregation propensity. In view of this fact, we found it more insightful to delve into the connection between structure and stability under sub-aggregating conditions (10% TFE). In the absence of the co-solvent, the abridged variants display a common native-like region decorated with a disordered C-terminal stretch. Upon TFE addition, an increase in secondary structure content is observed, assimilating them to the parent protein. In this sense, TFE perturbs a common native like region while exerting a global compaction effect. Importantly, in all cases, fatty acid binding function is preserved. Interestingly, energetic as well as structural diversity in aqueous solution evolves into a common conformational ensemble more akin in stability. These facts reconcile apparent paradoxical findings related to stability and rates of aggregation. This scenario likely mimics the accrual of aggregation-prone species in the population, an early critical event for the development of fibrillation. |
| format | Article |
| id | doaj-art-bde0925f98d542ffaa1ca1c91a22c293 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-bde0925f98d542ffaa1ca1c91a22c2932025-08-20T02:46:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017060710.1371/journal.pone.0170607Structural coalescence underlies the aggregation propensity of a β-barrel protein motif.Carla R AngelaniJulio J CarameloLucrecia M CurtoJosé M DelfinoA clear understanding of the structural foundations underlying protein aggregation is an elusive goal of central biomedical importance. A step toward this aim is exemplified by the β-barrel motif represented by the intestinal fatty acid binding protein (IFABP) and two abridged all-β sheet forms (Δ98Δ and Δ78Δ). At odds with the established notion that a perturbation of the native fold should necessarily favor a buildup of intermediate forms with an enhanced tendency to aggregate, the intrinsic stability (ΔG°H2O) of these proteins does not bear a straightforward correlation with their trifluoroethanol (TFE)-induced aggregation propensity. In view of this fact, we found it more insightful to delve into the connection between structure and stability under sub-aggregating conditions (10% TFE). In the absence of the co-solvent, the abridged variants display a common native-like region decorated with a disordered C-terminal stretch. Upon TFE addition, an increase in secondary structure content is observed, assimilating them to the parent protein. In this sense, TFE perturbs a common native like region while exerting a global compaction effect. Importantly, in all cases, fatty acid binding function is preserved. Interestingly, energetic as well as structural diversity in aqueous solution evolves into a common conformational ensemble more akin in stability. These facts reconcile apparent paradoxical findings related to stability and rates of aggregation. This scenario likely mimics the accrual of aggregation-prone species in the population, an early critical event for the development of fibrillation.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0170607&type=printable |
| spellingShingle | Carla R Angelani Julio J Caramelo Lucrecia M Curto José M Delfino Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. PLoS ONE |
| title | Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. |
| title_full | Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. |
| title_fullStr | Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. |
| title_full_unstemmed | Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. |
| title_short | Structural coalescence underlies the aggregation propensity of a β-barrel protein motif. |
| title_sort | structural coalescence underlies the aggregation propensity of a β barrel protein motif |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0170607&type=printable |
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