Journal article
Structural basis for Aβ1–42 toxicity inhibition by Aβ C-terminal fragments: Discrete molecular dynamics study
Journal of molecular biology, v 410(2), pp 316-328
08 Jul 2011
PMID: 21621545
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Amyloid β-protein (Aβ) is central to the pathology of Alzheimer’s disease (AD). Of the two predominant Aβ alloforms, Aβ
1–40
and Aβ
1–42
, the latter forms more toxic oligomers. C-terminal fragments (CTFs) of Aβ were recently shown to inhibit Aβ
1–42
toxicity
in vitro
. Here we studied Aβ
1–42
assembly in the presence of three effective CTF inhibitors and an ineffective fragment, Aβ
21–30
. Using a discrete molecular dynamics approach that recently was shown to capture key differences between Aβ
1–40
and Aβ
1–42
oligomerization, we compared Aβ
1–42
oligomer formation in the absence and presence of CTFs or Aβ
21–30
and identified structural elements of Aβ
1–42
that correlated with Aβ
1–42
toxicity. CTFs co-assembled with Aβ
1–42
into large heterooligomers containing multiple Aβ
1–42
and inhibitor fragments. In contrast, Aβ
21–30
co-assembled with Aβ
1–42
into heterooligomers containing mostly a single Aβ
1–42
and multiple Aβ
21–30
fragments. The CTFs, but not Aβ
21–30
, decreased the β-strand propensity of Aβ
1–42
in a concentration-dependent manner. CTFs and Aβ
21–30
had a high binding propensity to the hydrophobic regions of Aβ
1–42
but only CTFs were found to bind the Aβ
1–42
region A2-F4. Consequently, only CTFs but not Aβ
21–30
reduced the solvent accessibility of Aβ
1–42
in the region D1-R5. The reduced solvent accessibility of Aβ
1–42
in the presence of CTFs was comparable to the solvent accessibility of Aβ
1–40
oligomers formed in the absence of Aβ fragments. These findings suggest that the region D1-R5, which was more exposed to the solvent in Aβ
1–42
than in Aβ
1–40
oligomers, is involved in mediating Aβ
1–42
oligomer neurotoxicity.
Metrics
Details
- Title
- Structural basis for Aβ1–42 toxicity inhibition by Aβ C-terminal fragments: Discrete molecular dynamics study
- Creators
- B Urbanc - Department of Physics, Drexel University, Philadelphia, PA 19104, USAM Betnel - Department of Physics, Boston University, Boston, MA 02215, USAL Cruz - Department of Physics, Drexel University, Philadelphia, PA 19104, USAH Li - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7334, USAE.A Fradinger - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7334, USAB.H Monien - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7334, USAG Bitan - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7334, USA
- Publication Details
- Journal of molecular biology, v 410(2), pp 316-328
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000292783000010
- Scopus ID
- 2-s2.0-79958703402
- Other Identifier
- 991014877716804721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology