Abstract:
:It has been well established that a single amino acid sequence can give rise to several conformationally distinct amyloid states. The extent to which amyloid structures formed within the same sequence are different, however, remains unclear. To address this question, we studied two amyloid states (referred to as R- and S-fibrils) produced in vitro from highly purified full-length recombinant prion protein. Several biophysical techniques including X-ray diffraction, CD, Fourier transform infrared spectroscopy (FTIR), hydrogen-deuterium exchange, proteinase K digestion, and binding of a conformation-sensitive fluorescence dye revealed that R- and S-fibrils have substantially different secondary, tertiary, and quaternary structures. While both states displayed a 4. 8-A meridional X-ray diffraction typical for amyloid cross-beta-spines, they showed markedly different equatorial profiles, suggesting different folding pattern of beta-strands. The experiments on hydrogen-deuterium exchange monitored by FTIR revealed that only small fractions of amide protons were protected in R- or S-fibrils, an argument for the dynamic nature of their cross-beta-structure. Despite this fact, both amyloid states were found to be very stable conformationally as judged from temperature-induced denaturation monitored by FTIR and the conformation-sensitive dye. Upon heating to 80 degrees C, only local unfolding was revealed, while individual state-specific cross-beta features were preserved. The current studies demonstrated that the two amyloid states formed by the same amino acid sequence exhibited significantly different folding patterns that presumably reflect two different architectures of cross-beta-structure. Both S- and R-fibrils, however, shared high conformational stability, arguing that the energy landscape for protein folding and aggregation can contain several deep free-energy minima.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Ostapchenko VG,Sawaya MR,Makarava N,Savtchenko R,Nilsson KP,Eisenberg D,Baskakov IVdoi
10.1016/j.jmb.2010.05.051subject
Has Abstractpub_date
2010-07-23 00:00:00pages
908-21issue
4eissn
0022-2836issn
1089-8638pii
S0022-2836(10)00555-3journal_volume
400pub_type
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