Journal article
Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization
Journal of biological physics, v 42(3), pp 453-476
Jun 2016
PMID: 27155979
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Amyloid
β
-protein (A
β
) assembles into oligomers that play a seminal role in Alzheimer’s disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of A
β
oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant A
β
alloforms in the brain, A
β
40
and A
β
42
, whereas the [K28A] substitution exerts only a moderate effect. Here, folding and oligomerization of [A16]A
β
40
, [A28]A
β
40
, [A16]A
β
42
, and [A28]A
β
42
are examined by discrete molecular dynamics (DMD) combined with a four-bead implicit solvent force field, DMD4B-HYDRA, and compared to A
β
40
and A
β
42
oligomer formation. Our results show that both substitutions promote A
β
40
and A
β
42
oligomerization and that structural changes to oligomers are substitution- and alloform-specific. The [K28A] substitution increases solvent-accessible surface area of hydrophobic residues and the intrapeptide N-to-C terminal distance within oligomers more than the [K16A] substitution. The [K16A] substitution decreases the overall
β
-strand content, whereas the [K28A] substitution exerts only a modest change. Substitution-specific tertiary and quaternary structure changes indicate that the [K16A] substitution induces formation of more compact oligomers than the [K28A] substitution. If the structure-function paradigm applies to A
β
oligomers, then the observed substitution-specific structural changes in A
β
40
and A
β
42
oligomers are critical for understanding the structural basis of A
β
oligomer toxicity and correct identification of therapeutic targets against AD.
Metrics
Details
- Title
- Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization
- Creators
- Matjaž žganec - Faculty of Mathematics and Physics, Jadranska ulica 19, 1000 Ljubljana, SloveniaNicholas Kruczek - Drexel University, 3141 Chestnut St., Philadelphia, PA 19104 USABrigita Urbanc - Faculty of Mathematics and Physics, Jadranska ulica 19, 1000 Ljubljana, Slovenia
- Publication Details
- Journal of biological physics, v 42(3), pp 453-476
- Publisher
- Springer Netherlands; Dordrecht
- Grant note
- TG-PHYS100030 / ; 11012-37/2014; 11012-32/2015 / ;
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000379922500011
- Scopus ID
- 2-s2.0-84966297028
- Other Identifier
- 991014877920704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biophysics