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首页> 外文学位 >Analysis of the function of cleavage and conformation of Epstein-Barr virus glycoproteins gB and gp42 in membrane fusion.
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Analysis of the function of cleavage and conformation of Epstein-Barr virus glycoproteins gB and gp42 in membrane fusion.

机译：膜融合中爱泼斯坦-巴尔病毒糖蛋白gB和gp42的裂解和构象功能分析。

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摘要

Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with infectious mononucleosis as well as malignancies of epithelial and B cell origin. EBV entry into epithelial and B cells requires glycoproteins gB, gH, and gL. EBV gB possesses a conserved furin cleavage motif and cleaved gB is present in EBV virions. The EBV gB furin cleavage motif was deleted by site-directed mutagenesis. Elimination of the gB cleavage motif reduced EBV-induced fusion with both epithelial and B cells in a cell fusion assay, with a greater effect on epithelial cell fusion observed. Proximal deletions of identical size on either side of the gB cleavage motif had no effect on fusion with either cell type. The observed decrease in cell fusion with the gB cleavage mutant is similar to that observed with multiple alphaherpesvirus gB cleavage mutants and supports a conserved function for cleaved gB.;For EBV entry into B cells, an additional glycoprotein, gp42, is required. EBV gp42 occurs in two forms, a full-length membrane-bound form and a soluble form generated by proteolytic cleavage, which is secreted from infected cells due to loss of the transmembrane domain. The functional significance of gp42 cleavage is currently unclear. To better understand the role of gp42 in membrane fusion, gp42 cleavage site mutants were assayed for ability to mediate fusion with B cells. In a cell fusion assay, enhanced secretion of gp42 promoted fusion, while gp42 cleavage site mutation inhibited fusion, suggesting that cleavage and secretion of gp42 is necessary for B-cell membrane fusion. These observations provide the first indicated functional difference between full-length and soluble gp42.;The recently solved crystal structure of unbound EBV gp42 allowed comparison to the structure of receptor-bound gp42. Conformational changes between the two structures, specifically around the gp42 hydrophobic pocket, suggested a structural mechanism for gp42 triggering of membrane fusion. Structure-based EBV gp42 mutants were constructed and assayed for receptor binding and membrane fusion activity. Some of the mutations had significant effects on these processes, but further study is necessary to determine the specific relationship between the observed gp42 conformational changes and membrane fusion activation.
机译：爱泼斯坦-巴尔病毒（EBV）是与传染性单核细胞增多以及上皮和B细胞起源的恶性肿瘤相关的人γ疱疹病毒。 EBV进入上皮和B细胞需要糖蛋白gB，gH和gL。 EBV gB具有保守的弗林蛋白酶切割基序，并且切割的gB存在于EBV病毒体中。 EBV gB弗林蛋白酶切割基序被定点诱变删除。在细胞融合测定中，gB切割基序的消除减少了EBV诱导的与上皮细胞和B细胞的融合，观察到的对上皮细胞融合的更大影响。在gB裂解基序两侧的相同大小的近端缺失对与任一细胞类型的融合均无影响。观察到的与gB裂解突变体融合的细胞减少与多个α疱疹病毒gB裂解突变体观察到的相似，并且支持裂解的gB的保守功能;对于EBV进入B细胞，还需要另外的糖蛋白gp42。 EBV gp42有两种形式，一种是全长的膜结合形式，另一种是通过蛋白水解切割产生的可溶形式，由于跨膜结构域的丧失，这种形式从感染细胞中分泌出来。目前尚不清楚gp42切割的功能意义。为了更好地理解gp42在膜融合中的作用，分析了gp42切割位点突变体介导与B细胞融合的能力。在细胞融合测定中，gp42分泌的增加促进融合，而gp42裂解位点突变抑制融合，这表明gp42的裂解和分泌对于B细胞膜融合是必需的。这些观察结果提供了全长gp42和可溶性gp42之间的首次指出的功能差异。最近解决的未结合的EBV gp42的晶体结构允许与受体结合的gp42的结构进行比较。两种结构之间的构象变化，特别是在gp42疏水口袋周围，提示了gp42触发膜融合的结构机制。构建基于结构的EBV gp42突变体，并分析其受体结合和膜融合活性。一些突变对这些过程有重大影响，但需要进一步的研究来确定观察到的gp42构象变化与膜融合激活之间的特定关系。

著录项

  • 作者

    Sorem, Jessica.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Molecular.;Biology Virology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 167 p.
  • 总页数 167
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:30

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