Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 124, Issue 47, Pages 10708-10717Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.0c08280
Keywords
-
Categories
Funding
- National Science Foundation [MCB160005]
- National Institutes of Health [GM120634]
Ask authors/readers for more resources
In systemic amyloidosis, serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure been resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a 2-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23-51) but is not affected by the presence of the disordered C-terminal tail.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available