TY - JOUR
T1 - Interaction of aβ42 with membranes triggers the self-assembly into oligomers
AU - Banerjee, Siddhartha
AU - Hashemi, Mohtadin
AU - Zagorski, Karen
AU - Lyubchenko, Yuri L.
N1 - Funding Information:
Funding: This research was funded by National Institutes of Health, grants GM096039 and GM118006 to Y.L.L. Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health.
Funding Information:
Acknowledgments: The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. This work was completed utilizing the Holland Computing Center of the University of Nebraska, which receives support from the Nebraska Research Initiative.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations-a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide–membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations.
AB - The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations-a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide–membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations.
KW - Alzheimer’s disease
KW - Amyloid aggregation
KW - Molecular dynamics simulation
KW - Supported lipid bilayers
KW - Time-lapse AFM
UR - http://www.scopus.com/inward/record.url?scp=85079310226&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079310226&partnerID=8YFLogxK
U2 - 10.3390/ijms21031129
DO - 10.3390/ijms21031129
M3 - Article
C2 - 32046252
AN - SCOPUS:85079310226
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 3
M1 - 1129
ER -