The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function
文献类型：期刊论文
| 作者 | Lan, K; Dong, YH ; Hu ML(胡梦璐); Dong YH(董宇辉); Yuan, F; Gao ZQ(高增强); Gao, ZQ; Majerciak, V; Bai, L; Hu, ML
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| 刊名 | PLOS PATHOGENS
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| 出版日期 | 2018 |
| 卷号 | 14期号:8页码:e1007232 |
| ISSN号 | 1553-7366 |
| DOI | 10.1371/journal.ppat.1007232 |
| 文献子类 | Article |
| 英文摘要 | Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-herpesvirus closely associated with Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman disease. Open reading frame 57 (ORF57), a viral early protein of KSHV promotes splicing, stability and translation of viral mRNA and is essential for viral lytic replication. Previous studies demonstrated that dimerization of ORF57 stabilizes the protein, which is critical for its function. However, the detailed structural basis of dimerization was not elucidated. In this study, we report the crystal structures of the C-terminal domain (CTD) of ORF57 (ORF57-CTD) in both dimer at 3.5 angstrom and monomer at 3.0 angstrom. Both structures reveal that ORF57-CTD binds a single zinc ion through the consensus zinc-binding motif at the bottom of each monomer. In addition, the N-terminal residues 167-222 of ORF57-CTD protrudes a long "arm" and holds the globular domains of the neighboring monomer, while the C-terminal residues 445-454 are locked into the globular domain in cis and the globular domains interact in trans. In vitro crosslinking and nuclear translocation assays showed that either deletion of the "arm" region or substitution of key residues at the globular interface led to severe dimer dissociation. Introduction of point mutation into the zinc-binding motif also led to sharp degradation of KSHV ORF57 and other herpesvirus homologues. These data indicate that the "arm" region, the residues at the globular interface and the zinc-binding motif are all equally important in ORF57 protein dimerization and stability. Consistently, KSHV recombinant virus with the disrupted zinc-binding motif by point mutation exhibited a significant reduction in the RNA level of ORF57 downstream genes ORF59 and K8.1 and infectious virus production. Taken together, this study illustrates the first structure of KSHV ORF57-CTD and provides new insights into the understanding of ORF57 protein dimerization and stability, which would shed light on the potential design of novel therapeutics against KSHV infection and related diseases. |
| 电子版国际标准刊号 | 1553-7374 |
| WOS关键词 | HIV-1 NUCLEOCAPSID PROTEIN ; HUMAN CYTOMEGALOVIRUS PROTEASE ; MESSENGER-RNA EXPORT ; KAPOSIS-SARCOMA ; HERPESVIRUS ORF57 ; DNA-SEQUENCES ; 3-DIMENSIONAL STRUCTURE ; INFECTIOUS VIRUS ; ZINC FINGERS ; CELL-LINE |
| WOS研究方向 | Microbiology ; Parasitology ; Virology |
| 语种 | 英语 |
| WOS记录号 | WOS:000443296800028 |
| 源URL | [http://ir.ihep.ac.cn/handle/311005/286267]  |
| 专题 | 高能物理研究所_多学科研究中心 |
| 通讯作者 | Dong YH(董宇辉) |
| 作者单位 | 中国科学院高能物理研究所 |
| 推荐引用方式 GB/T 7714 | Lan, K,Dong, YH,Hu ML,et al. The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function[J]. PLOS PATHOGENS,2018,14(8):e1007232. |
| APA | Lan, K.,Dong, YH.,胡梦璐.,董宇辉.,Yuan, F.,...&Zheng, ZM.(2018).The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function.PLOS PATHOGENS,14(8),e1007232. |
| MLA | Lan, K,et al."The crystal structure of KSHV ORF57 reveals dimeric active sites important for protein stability and function".PLOS PATHOGENS 14.8(2018):e1007232. |
入库方式： OAI收割
来源：高能物理研究所
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