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Atomic Resolution Structure of Monomorphic A?42 Amyloid Fibrils
#MMPMID27355699
Colvin MT
; Silvers R
; Ni QZ
; Can TV
; Sergeyev I
; Rosay M
; Donovan KJ
; Michael B
; Wall J
; Linse S
; Griffin RG
J Am Chem Soc
2016[Aug]; 138
(30
): 9663-74
PMID27355699
show ga
Amyloid-? (A?) is a 39-42 residue protein produced by the cleavage of the amyloid
precursor protein (APP), which subsequently aggregates to form cross-? amyloid
fibrils that are a hallmark of Alzheimer's disease (AD). The most prominent forms
of A? are A?1-40 and A?1-42, which differ by two amino acids (I and A) at the
C-terminus. However, A?42 is more neurotoxic and essential to the etiology of AD.
Here, we present an atomic resolution structure of a monomorphic form of A?M01-42
amyloid fibrils derived from over 500 (13)C-(13)C, (13)C-(15)N distance and
backbone angle structural constraints obtained from high field magic angle
spinning NMR spectra. The structure (PDB ID: 5KK3 ) shows that the fibril core
consists of a dimer of A?42 molecules, each containing four ?-strands in a
S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic
cores that are capped at the end of the chain by a salt bridge. The outer surface
of the monomers presents hydrophilic side chains to the solvent. The interface
between the monomers of the dimer shows clear contacts between M35 of one
molecule and L17 and Q15 of the second. Intermolecular (13)C-(15)N constraints
demonstrate that the amyloid fibrils are parallel in register. The RMSD of the
backbone structure (Q15-A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ±
0.08 Å. The structure provides a point of departure for the design of drugs that
bind to the fibril surface and therefore interfere with secondary nucleation and
for other therapeutic approaches to mitigate A?42 aggregation.
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