Abstract:
:Recent cryoEM density maps of Abeta(42) fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular Abeta(42) fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations.
journal_name
Proc Natl Acad Sci U S Aauthors
Miller Y,Ma B,Tsai CJ,Nussinov Rdoi
10.1073/pnas.1004704107subject
Has Abstractpub_date
2010-08-10 00:00:00pages
14128-33issue
32eissn
0027-8424issn
1091-6490pii
1004704107journal_volume
107pub_type
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