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Hydrogen/Deuterium Exchange and Molecular Dynamics Analysis of Amyloid Fibrils Formed by a D69K Charge-Pair Mutant of Human Apolipoprotein C-II.
- Source :
-
Biochemistry . 8/11/2015, Vol. 54 Issue 31, p4805-4814. 6p. - Publication Year :
- 2015
-
Abstract
- Plasma apolipoproteins form amphipathic a helices in lipid environments but in the lipid-free state show a high propensity to form β structure and self-associate into amyloid fibrils. The widespread occurrence of apolipoproteins in amyloid plaques suggests disease-related roles, specifically in atherosclerosis. To reconcile the dual abilities of apolipoproteins to form either a helices or cross-β sheet structures, we examined fibrils formed by human apolipoprotein C-II (apoC-II). A structural model for apoC-II fibrils shows a cross-β core with parallel ft strands, including a buried K30-D69 charge pair. We investigated the effect of abolishing this charge pair in mutant D69K apoC-II. Fluorescence studies indicated more rapid fibril formation and less solvent accessibility of tryptophan (W26) in D69K apoC-II fibrils than in wild-type (WT) fibrils. X-ray diffraction data of aligned D69K apoC-II fibrils yielded a typical cross-β structure with increased ft sheet spacing compared to that of WT fibrils. Hydrogen/deuterium (H /D) exchange patterns were similar for D69K apoC-II fibrils compared to WT fibrils, albeit with an overall reduction in the level of slow H /D exchange, particularly around residues 29--32. Molecular dynamics simulations indicated reducedβ strand content for a model D69K apoC-II tetramer compared to the WT tetramer and confirmed an expansion of the cross-β spacing that contributed to the formation of a stable charge pair between K69 and E27. The results highlight the importance of charge-pair interactions within the apoC-II fibril core, which together with numerous salt bridges in the flexible connecting loop play a major role in tire ability of lipid-free apoC-II to form stable cross-β fibrils. [ABSTRACT FROM AUTHOR]
- Subjects :
- *HYDROGEN
*DEUTERIUM
*MOLECULAR dynamics
*AMYLOID
*GLYCOPROTEINS
*APOLIPOPROTEIN C
Subjects
Details
- Language :
- English
- ISSN :
- 00062960
- Volume :
- 54
- Issue :
- 31
- Database :
- Academic Search Index
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 109139892
- Full Text :
- https://doi.org/10.1021/acs.biochem.5b00535