Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio.
Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio.
复制标题
DOI：
10.1038/srep16912
复制
发表时间：
2015-11-18
影响因子：
4.6
通讯作者：
Baskakov IV
中科院分区：
文献类型：
--
作者：
Katorcha E;Makarava N;Savtchenko R;Baskakov IV
朊病毒或PrPSc是一种蛋白质感染因子，由称为朊病毒蛋白或PrPC的唾液酸糖蛋白的错误折叠和聚集形式组成。PrPC具有两个唾液酸化的N-连接的碳水化合物。在PrPSc中，聚糖向外定向，末端唾液酸残基在朊病毒颗粒表面上产生负电荷。目前的研究提出了一个新的假设，唾液酸残基之间的静电排斥产生的结构限制，控制朊病毒复制和PrPSc糖型比例。在支持这一假设，在这里，我们表明，二糖基化的PrPC分子，每个分子比单糖基化的PrPC具有更多的唾液酸基团，优先排除转换。然而，当部分去唾液酸化的PrPC被用作基板，招聘三糖型到PrPSc被发现是成比例的基板中的各自的人口。此外，在结构限制最强的菌株中，过度唾液酸化分子也被排除在转化之外，这一策略有助于减少静电排斥。此外，如所预测的假设，部分去唾液酸化的PrPC显着增加复制率。这项研究表明，唾液酸化的N-连接聚糖创建一个朊病毒复制障碍，控制复制速率和糖型比例，并具有广泛的影响。
Prion or PrPSc is a proteinaceous infectious agent that consists of a misfolded and aggregated form of a sialoglycoprotein called prion protein or PrPC. PrPC has two sialylated N-linked carbohydrates. In PrPSc, the glycans are directed outward, with the terminal sialic acid residues creating a negative charge on the surface of prion particles. The current study proposes a new hypothesis that electrostatic repulsion between sialic residues creates structural constraints that control prion replication and PrPSc glycoform ratio. In support of this hypothesis, here we show that diglycosylated PrPC molecules that have more sialic groups per molecule than monoglycosylated PrPC were preferentially excluded from conversion. However, when partially desialylated PrPC was used as a substrate, recruitment of three glycoforms into PrPSc was found to be proportional to their respective populations in the substrate. In addition, hypersialylated molecules were also excluded from conversion in the strains with the strongest structural constraints, a strategy that helped reduce electrostatic repulsion. Moreover, as predicted by the hypothesis, partial desialylation of PrPC significantly increased the replication rate. This study illustrates that sialylation of N-linked glycans creates a prion replication barrier that controls replication rate and glycoform ratios and has broad implications.