Comparative Studies of Disordered Proteins with Similar Sequences: Application to Aβ40 and Aβ42
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Fisher-2013-Comparative Studies.pdf
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Author(s)
Fisher, Charles K.
Ullman, Orly
Stultz, Collin M.
Date Issued
April 2013
Journal
Biophysical Journal
Publisher
Elsevier B.V.
Citation
Fisher, Charles K., Orly Ullman, and Collin M. Stultz. “Comparative Studies of Disordered Proteins with Similar Sequences: Application to Aβ40 and Aβ42.” Biophysical Journal 104, no. 7 (April 2013): 1546–1555.
Version
Final published version
Abstract
Quantitative comparisons of intrinsically disordered proteins (IDPs) with similar sequences, such as mutant forms of the same protein, may provide insights into IDP aggregation—a process that plays a role in several neurodegenerative disorders. Here we describe an approach for modeling IDPs with similar sequences that simplifies the comparison of the ensembles by utilizing a single library of structures. The relative population weights of the structures are estimated using a Bayesian formalism, which provides measures of uncertainty in the resulting ensembles. We applied this approach to the comparison of ensembles for Aβ40 and Aβ42. Bayesian hypothesis testing finds that although both Aβ species sample β-rich conformations in solution that may represent prefibrillar intermediates, the probability that Aβ42 samples these prefibrillar states is roughly an order of magnitude larger than the frequency in which Aβ40 samples such structures. Moreover, the structure of the soluble prefibrillar state in our ensembles is similar to the experimentally determined structure of Aβ that has been implicated as an intermediate in the aggregation pathway. Overall, our approach for comparative studies of IDPs with similar sequences provides a platform for future studies on the effect of mutations on the structure and function of disordered proteins.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Research Laboratory of Electronics
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DOI of Published Version
https://doi.org/10.1016/j.bpj.2013.02.023
