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PDBsum entry 2e8d
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Protein fibril, immune system
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PDB id
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2e8d
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References listed in PDB file
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Key reference
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Title
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3d structure of amyloid protofilaments of beta2-Microglobulin fragment probed by solid-State nmr.
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Authors
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K.Iwata,
T.Fujiwara,
Y.Matsuki,
H.Akutsu,
S.Takahashi,
H.Naiki,
Y.Goto.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
18119-18124.
[DOI no: ]
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PubMed id
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Abstract
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Understanding the structure and formation of amyloid fibrils, the filamentous
aggregates of proteins and peptides, is crucial in preventing diseases caused by
their deposition and, moreover, for obtaining further insight into the mechanism
of protein folding and misfolding. We have combined solid-state NMR, x-ray fiber
diffraction, and atomic force microscopy to reveal the 3D structure of amyloid
protofilament-like fibrils formed by a 22-residue K3 peptide (Ser(20)-Lys(41))
of beta(2)-microglobulin, a protein responsible for dialysis-related
amyloidosis. Although a uniformly (13)C,(15)N-labeled sample was used for the
NMR measurements, we could obtain the 3D structure of the fibrils on the basis
of a large number of structural constraints. The conformation of K3 fibrils was
found to be a beta-strand-loop-beta-strand with each K3 molecule stacked in a
parallel and staggered manner. It is suggested that the fibrillar conformation
is stabilized by intermolecular interactions, rather than by intramolecular
hydrophobic packing as seen in globular proteins. Together with thermodynamic
studies of the full-length protein, formation of the fibrils is likely to
require side chains on the intermolecular surface to pack tightly against those
of adjacent monomers. By revealing the structure of beta(2)-microglobulin
protofilament-like fibrils, this work represents technical progress in analyzing
amyloid fibrils in general through solid-state NMR.
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Figure 1.
Fig. 1. AFM images and x-ray fiber diffraction of K3
fibrils. (A) AFM images of K3 fibrils formed in 20% (vol/vol)
TFE/10 mM HCl. The scan was performed with a 25-fold diluted
sample on a freshly cleaved mica surface. The white scale bar
represents 500 nm, and the scan size is 2.5 x 2.5 µm with
512 x 512 points. (B) X-ray fiber diffraction of the K3 fibrils
with incident beam perpendicular to the fibril axis. The data
shows a typical cross-  pattern. The
diffractions corresponding to 4.72 Å (red) and 9.52
Å (blue) indicate the distance between -strands in the -sheet
and -sheet layers in the
laminated structure, respectively.
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Figure 5.
Fig. 5. 3D structures of tetrameric K3 and monomeric K3 in
the fibrillar state. The conformation of K3 in the fibrillar
state obtained by simulated annealing molecular dynamics by
using CNS. (A) Calculated ensemble of tetrameric structures of
K3 fibrils. (B) Ribbon model representation of tetrameric K3 in
parallel STAG(+1) conformation. (C) The conformation of one K3
structure in the fibrillar state. (D) Comparison of the
conformation of the K3 region in the crystal structure of native
2-m.
Notably, the residues between Phe^22 and Ser^28 are flipped
relative to the crystal structure of native 2-m in the fibrillar
state.
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