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Molecular conformation and dynamics of the Y145Stop variant of human prion protein
被引:159
作者:
Helmus, Jonathan J.
[3
]
Surewicz, Krystyna
[1
]
Nadaud, Philippe S.
[3
]
Surewicz, Witold K.
[1
,2
]
Jaroniec, Christopher P.
[3
]
机构:
[1] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA
[3] Ohio State Univ, Dept Chem, Columbus, OH 43210 USA
来源:
关键词:
protein structure;
solid-state NMR;
protein misfolding;
transmissible spongiform encephalopathies;
D O I:
10.1073/pnas.0711716105
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
A C-terminally truncated Y145Stop variant of the human prion protein (huPrP23-144) is associated with a hereditary amyloid disease known as PrP cerebral amyloid angiopathy. Previous studies have shown that recombinant huPrP23-144 can be efficiently converted in vitro to the fibrillar amyloid state, and that residues 138 and 139 play a critical role in the amyloidogenic properties of this protein. Here, we have used magic-angle spinning solid-state NMR spectroscopy to provide high-resolution insight into the protein backbone conformation and dynamics in fibrils formed by C-13,N-15-labeled huPrP23-144. Surprisingly, we find that signals from approximate to 100 residues (i.e., approximate to 80% of the sequence) are not detected above approximately -20 degrees C in conventional solid-state NMR spectra. Sequential resonance assignments revealed that signals, which are observed, arise exclusively from residues in the region 112-141. These resonances are remarkably narrow, exhibiting average C-13 and N-15 linewidths of approximate to 0.6 and 1 ppm, respectively. Altogether, the present findings indicate the existence of a compact, highly ordered core of huPrP23-144 amyloid encompassing residues 112-141. Analysis of 13C secondary chemical shifts identified likely beta-strand segments within this core region, including beta-strand 130-139 containing critical residues 138 and 139. In contrast to this relatively rigid, beta-sheet-rich amyloid core, the remaining residues in huPrP23-144 amyloid fibrils under physiologically relevant conditions are largely unordered, displaying significant conformational dynamics.
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页码:6284 / 6289
页数:6
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