Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation
Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation
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DOI：
10.1074/jbc.m115.665844
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发表时间：
2015-08-28
影响因子：
4.8
通讯作者：
Caughey, Byron
中科院分区：
文献类型：
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作者：
Kraus, Allison;Anson, Kelsie J.;Caughey, Byron
背景：我们研究了致病性朊蛋白突变P102 L和P105 L如何导致错误折叠。结果：这些脯氨酸和邻近的赖氨酸残基的突变加速了体外淀粉样蛋白的形成，其性质让人联想到PrPSc。结论：特异性脯氨酸和赖氨酸残基可能通过阻止PrP转化为淀粉样蛋白而延缓自发性朊病毒病。重要性：这些发现提示了遗传性朊病毒疾病的机制。人类朊病毒疾病可以有获得性、散发性或遗传性起源，每种起源都导致朊病毒蛋白（PrP）转化为可传播的病理形式。遗传性朊病毒疾病Gerstmann-Straussler-Scheinker综合征可由脯氨酸102或105的点突变引起。然而，这两个脯氨酸，其突变，对PrP错误折叠的结构影响还没有很好地理解。在这里，我们提供的证据表明，个别突变的Pro-102或Pro-105的非环状脂肪族残基，如Gerstmann-Straussler-Scheinker连接的亮氨酸可以促进在体外形成的PrP淀粉样蛋白与延长的蛋白酶耐核心的感染性朊病毒。这种效果增强了额外的电荷中和突变的四个附近的赖氨酸残基组成的所谓的中央赖氨酸簇。取代这些脯氨酸和赖氨酸残基加速PrP的转换，使自发的淀粉样蛋白的形成不再慢于痒病种子淀粉样蛋白的形成。因此，Pro-102和Pro-105以及中心赖氨酸簇中的赖氨酸阻碍PrP形成淀粉样蛋白，暗示这些残基是PrP转化为疾病相关类型淀粉样蛋白的关键结构调节剂。
Background: We investigated how pathogenic prion protein mutations P102L and P105L lead to misfolding. Results: Mutations of these proline and adjacent lysine residues accelerated in vitro formation of amyloid with properties reminiscent of PrPSc. Conclusion: Specific proline and lysine residues might delay spontaneous prion disease by hindering PrP conversion into amyloid. Significance: These findings suggest mechanisms for genetic prion diseases.Human prion diseases can have acquired, sporadic, or genetic origins, each of which results in the conversion of prion protein (PrP) to transmissible, pathological forms. The genetic prion disease Gerstmann-Straussler-Scheinker syndrome can arise from point mutations of prolines 102 or 105. However, the structural effects of these two prolines, and mutations thereof, on PrP misfolding are not well understood. Here, we provide evidence that individual mutations of Pro-102 or Pro-105 to noncyclic aliphatic residues such as the Gerstmann-Straussler-Scheinker-linked leucines can promote the in vitro formation of PrP amyloid with extended protease-resistant cores reminiscent of infectious prions. This effect was enhanced by additional charge-neutralizing mutations of four nearby lysine residues comprising the so-called central lysine cluster. Substitution of these proline and lysine residues accelerated PrP conversion such that spontaneous amyloid formation was no longer slower than scrapie-seeded amyloid formation. Thus, Pro-102 and Pro-105, as well as the lysines in the central lysine cluster, impede amyloid formation by PrP, implicating these residues as key structural modulators in the conversion of PrP to disease-associated types of amyloid.