Structural Dynamics and Activity of B19V VP1u during the pHs of Cell Entry and Endosomal Trafficking.
Structural Dynamics and Activity of B19V VP1u during the pHs of Cell Entry and Endosomal Trafficking.
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DOI：
10.3390/v14091922
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发表时间：
2022-08-30
期刊：
影响因子：
--
通讯作者：
Agbandje-McKenna M
中科院分区：
文献类型：
--
作者：
Lakshmanan RV;Hull JA;Berry L;Burg M;Bothner B;McKenna R;Agbandje-McKenna M
细小病毒B19（B19 V）是一种人类病原体，是儿童第五种疾病的病原体。它也被认为会导致胎儿水肿，艾滋病患者贫血，以及镰状细胞病患者的短暂性再生障碍性危象。细小病毒（包括B19 V）的病毒蛋白1（VP 1u）的独特N-末端表现出磷脂酶A2（PLA 2）活性，这是内体逃逸所需的。呈现的是B19 V VP 1u在模拟细胞进入和内体运输至细胞核的pH条件下的结构动力学。使用圆二色性光谱，B19 V VP 1u的受体结合结构域显示出α-螺旋折叠，而PLA 2结构域显示出可能的熔融球状态，两者都是pH不变的。在内体pH下进行的差示扫描量热法显示，VP 1u PLA 2结构域的解链温度（Tm）在pH 7.4下被调节至体温（37 °C）。此外，在25-45 °C的温度范围内进行的PLA 2测定显示了温度和pH依赖性的活性变化。我们推测，VP 1u PLA 2结构域的Tm在不同的pH值的差异，使病毒“开关”的磷脂酶活性在衣壳贩运。此外，我们提出早期内体的环境作为内体逃逸导致B19 V感染的最佳条件。
Parvovirus B19 (B19V) is a human pathogen that is the causative agent of fifth disease in children. It is also known to cause hydrops in fetuses, anemia in AIDS patients, and transient aplastic crisis in patients with sickle cell disease. The unique N-terminus of Viral Protein 1 (VP1u) of parvoviruses, including B19V, exhibits phospholipase A2 (PLA2) activity, which is required for endosomal escape. Presented is the structural dynamics of B19V VP1u under conditions that mimic the pHs of cell entry and endosomal trafficking to the nucleus. Using circular dichroism spectroscopy, the receptor-binding domain of B19V VP1u is shown to exhibit an α-helical fold, whereas the PLA2 domain exhibits a probable molten globule state, both of which are pH invariant. Differential scanning calorimetry performed at endosomal pHs shows that the melting temperature (Tm) of VP1u PLA2 domain is tuned to body temperature (37 °C) at pH 7.4. In addition, PLA2 assays performed at temperatures ranging from 25–45 °C show both a temperature and pH-dependent change in activity. We hypothesize that VP1u PLA2 domain differences in Tm at differing pHs have enabled the virus to “switch on/off” the phospholipase activity during capsid trafficking. Furthermore, we propose the environment of the early endosome as the optimal condition for endosomal escape leading to B19V infection.
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