Full-length prion protein incorporated into prion aggregates is a marker for prion strain-specific destabilization of aggregate structure following cellular uptake.
Full-length prion protein incorporated into prion aggregates is a marker for prion strain-specific destabilization of aggregate structure following cellular uptake.
复制标题
掺入朊病毒聚集体中的全长朊病毒蛋白是细胞摄取后聚集体结构的朊病毒株特异性不稳定的标记。
DOI：
10.1093/jb/mvad032
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发表时间：
2023
影响因子：
2.7
通讯作者：
Priola,SuzetteA
中科院分区：
文献类型：
--
作者：
Shoup,Daniel;Priola,SuzetteA
通过蛋白酶敏感性朊病毒蛋白（PrPC）错误折叠成相同的感染性构象异构体而产生的感染性部分蛋白酶抗性朊病毒蛋白（PrPD）的不溶性聚集体的积累是朊病毒疾病的标志。聚集的PrPD被细胞吸收和降解，这一过程可能涉及聚集体结构的变化，可以通过全长PrPD的N-末端对细胞蛋白酶的可及性来监测。因此，我们跟踪蛋白酶的敏感性全长PrPD细胞摄取前和后的两个小鼠朊病毒株，22 L和87 V。对于这两种菌株，PrPD聚集体在细胞摄取后不太稳定，在大多数聚集体大小中，N-末端对细胞蛋白酶的可及性增加。然而，一个有限的大小范围内的聚集体能够更好地保护全长PrPD的N-末端，与22 L衍生的PrPD的N-末端比87 V的更受保护。有趣的是，聚集体结构的变化与PrPD蛋白酶耐药核心的最小变化相关。我们的数据表明，细胞不稳定的聚集体四级结构保护PrPD蛋白酶在应变依赖性的方式，与结构变化暴露蛋白酶敏感的PrPD蛋白酶抗性的核心，从而构象，聚集的PrPD几乎没有影响。
Accumulation of insoluble aggregates of infectious, partially protease-resistant prion protein (PrPD) generated via the misfolding of protease sensitive prion protein (PrPC) into the same infectious conformer, is a hallmark of prion diseases. Aggregated PrPDis taken up and degraded by cells, a process likely involving changes in aggregate structure that can be monitored by accessibility of the N-terminus of full-length PrPDto cellular proteases. We therefore tracked the protease sensitivity of full-length PrPDbefore and after cellular uptake for two murine prion strains, 22L and 87V. For both strains, PrPDaggregates were less stable following cellular uptake with increased accessibility of the N-terminus to cellular proteases across most aggregate sizes. However, a limited size range of aggregates was able to better protect the N-termini of full-length PrPD, with the N-terminus of 22L-derived PrPDmore protected than that of 87V. Interestingly, changes in aggregate structure were associated with minimal changes to the protease-resistant core of PrPD. Our data show that cells destabilize the aggregate quaternary structure protecting PrPDfrom proteases in a strain-dependent manner, with structural changes exposing protease sensitive PrPDhaving little effect on the protease-resistant core, and thus conformation, of aggregated PrPD.