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New Concept on the Phase Space of the Protein : Experiments and Theory

蛋白质相空间的新概念:实验与理论

基本信息

批准号：
14380314
负责人：
KUWATA Kazuo
金额：
$ 9.41万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

We found and structurally characterized the folding intermediate of hamster prion protein using high-pressure NMR method (K.Kuwata, Biochemistry, 2002) and designated it as PrP^*. We found that in PrP^*, B-and C-helices are preferentially disordered, while A-helix remains intact. Especially residues locate at the interface with the beta sheet (S2) are extremely unstable. It is highly possible that partially unfolded PrP^* is involved in the structural conversion reaction from PrP^C to PrP^<Sc>.We also clarified the three dimensional structure of oligomeric duster of PrP106-126, a peptide corresponding to the hydrophobic cluster of prion protein, using electron microscopy, circular dichroism, NMR and molecular dynamics simulation (K Kuwata Proc.Natl.Acad.Sci, 2003). The oligomeric conformation of PrP106-126 dusterwas stabilized by the hydrophobic interaction between methyl moieties.In hamster prion, residues exchanging on a time scale of micro-to milliseconds using CPMG relaxation dispersion method some what correspond to those exhibit low stability in high-pressure NMR method (Kuwata et al., Biochemistry, 2004). Moreover the distribution of those unstable residues is correlated with those involved in the causative mutation. Thus these residues may be responsible for the conformational conversion from PrPC to PrP^<Sc>.Furthermore we formulated a novel mathematical representation of the protein dynamics using the number theoretical description.

我们利用高压核磁共振技术(K.Kuwata，BioChemical，2002)发现并表征了仓鼠PrP蛋白的折叠中间体，命名为PrP^*。我们发现在PrP^*中，B-螺旋和C-螺旋优先无序，而A-螺旋保持不变。尤其是位于与β-折叠(S2)界面的残基极不稳定。PrP^*很可能参与了PrP^C到PrP^&lt；Sc&gt；的结构转换反应。我们还用电子显微镜、圆二色谱、核磁共振和分子动力学模拟(K Kuwata Proc.Natl.Academy.Sci，2003)阐明了PrP106-126寡聚体的三维结构。PrP106-126通过甲基基团之间的疏水相互作用稳定了PrP106-126的低聚构象。在仓鼠的Prion中，使用CPMG松弛分散方法在微秒到毫秒的时间尺度上交换残基，其中一些对应于高压核磁共振方法表现出的低稳定性(Kuwata等人，生物化学，2004)。此外，这些不稳定残基的分布与涉及致病突变的残基相关。因此，这些残基可能负责从PrPC到PrP^&lt；SC&gt；的构象转换。此外，我们利用数论描述建立了一种新的蛋白质动力学的数学表示。