Baidya, L and Reddy, G (2022) pH Induced Switch in the Conformational Ensemble of Intrinsically Disordered Protein Prothymosin-α and Its Implications for Amyloid Fibril Formation. In: Journal of Physical Chemistry Letters, 13 (41). pp. 9589-9598.
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Abstract
Aggregation of intrinsically disordered proteins (IDPs) can lead to neurodegenerative diseases. Although there is experimental evidence that acidic pH promotes IDP monomer compaction leading to aggregation, the general mechanism is unclear. We studied the pH effect on the conformational ensemble of prothymosin-α (proTα), which is involved in multiple essential functions, and probed its role in aggregation using computer simulations. We show that compaction in the proTα dimension at low pH is due to the protein's collapse in the intermediate region (E41-D80) rich in glutamic acid residues, enhancing its β-sheet content. We observed by performing dimer simulations that the conformations with high β-sheet content could act as aggregation-prone (N*) states and nucleate the aggregation process. The simulations initiated using N∗ states form dimers within a microsecond time scale, whereas the non-N∗ states do not form dimers within this time scale. This study contributes to understanding the general principles of pH-induced IDP aggregation.
Item Type: | Journal Article |
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Publication: | Journal of Physical Chemistry Letters |
Publisher: | American Chemical Society |
Additional Information: | The copyright for this article belongs to American Chemical Society. |
Keywords: | Amino acids; Compaction; Conformations; Neurodegenerative diseases; Proteins, Acidic pH; Aggregation process; Amyloid fibril formation; Conformational ensemble; Experimental evidence; Glutamic acid residues; Intrinsically disordered proteins; Protein collapse; Protein monomers; Time-scales, Dimers |
Department/Centre: | Division of Chemical Sciences > Solid State & Structural Chemistry Unit |
Date Deposited: | 04 Nov 2022 06:54 |
Last Modified: | 04 Nov 2022 06:54 |
URI: | https://eprints.iisc.ac.in/id/eprint/77660 |
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