Oligomers of the Prion Protein Fragment 106-126 Are Likely Assembled from β-Hairpins in Solution, and Methionine Oxidation Inhibits Assembly without Altering the Peptide's Monomeric Conformation
Oligomers of the Prion Protein Fragment 106-126 Are Likely Assembled from β-Hairpins in Solution, and Methionine Oxidation Inhibits Assembly without Altering the Peptide's Monomeric Conformation
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DOI：
10.1021/ja905595k
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发表时间：
2010-01-20
影响因子：
15
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
--
作者：
Grabenauer, Megan;Wu, Chun;Bowers, Michael T.
朊病毒蛋白PrP 106 -126的一部分在各种物种中高度保守，并且被认为是涉及蛋白质的淀粉样蛋白形成的关键结构域之一。我们使用离子迁移谱-质谱（IMS-MS）结合复制交换分子动力学（REMD）检查正常PrP 106 -126和两种非聚集形式的肽的单体和寡聚体结构，一种氧化形式，其中两个甲硫氨酸残基被氧化为甲硫氨酸亚砜，一种对照肽由与PrP 106 -126相同的氨基酸组成。我们的离子迁移率和模拟数据表明，正常和氧化肽的β-发夹单体的人口的存在。这得到了我们的CID数据的支持，表明正常肽的单体溶液含有类似于46%的β-折叠和类似于23%的β-转角含量，与我们的REMD模拟非常一致。通过IMS-MS仅观察到正常肽的寡聚化，而不是氧化肽或对照序列。我们的IMS-MS和CD数据都表明，这种低聚化是由有序的β-发夹单体而不是无序单体的缔合引起的。结构分析表明，正常和氧化的肽具有相似的二级和三级结构特性，这表明蛋氨酸氧化引起的聚集抑制源于介导肽间相互作用，而不是通过改变肽的单体构象。相反，相对于正常肽，α-螺旋和无规卷曲结构组分的增加可能是缺乏观察到的对照肽聚集的原因。
A portion of the prion protein, PrP106-126, is highly conserved among various species and is thought to be one of the key domains involving amyloid formation of the protein. We used ion mobility spectrometry-mass spectrometry (IMS-MS) in conjunction with replica exchange molecular dynamics (REMD) to examine the monomeric and oligomeric structures of normal PrP106-126 and two nonaggregating forms of the peptide, an oxidized form in which both methionine residues are oxidized to methionine sulfoxide and a control peptide consisting of the same amino acids as PrP106-126 in a scrambled sequence. Our ion mobility and simulation data indicate the presence of a population of beta-hairpin monomers for the normal and oxidized peptides. This is supported by our CID data indicating that a monomer solution of the normal peptide contains similar to 46% beta-sheet and similar to 23% beta-turn content, in excellent agreement with our REMD simulations. Oligomerization was seen by IMS-MS for the normal peptide only, not the oxidized peptide or the control sequence. Both our IMS-MS and CD data suggest that this oligomerization results from the association of ordered beta-hairpin monomers rather than disordered monomers. Structural analysis shows that the normal and oxidized peptides have similar secondary and tertiary structural properties, suggesting that the inhibition of aggregation caused by methionine oxidation stems from mediating interpeptide interactions rather than by altering the peptide's monomeric conformation. In contrast, an increase in alpha-helical and random coil structural components relative to the normal peptide might be responsible for the lack of observed aggregation of the control peptide.