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
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.
引用
收藏
页码:6284 / 6289
页数:6
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