{"title":"腺相关病毒复制蛋白 Rep78 含有一个在依赖性巴病毒中保存的严格的 C 端序列分子结构","authors":"David G Karlin","doi":"10.3390/v16111760","DOIUrl":null,"url":null,"abstract":"<p><p>Adeno-Associated Viruses (AAVs, genus <i>Dependoparvovirus</i>) are the leading gene therapy vector. Until recently, efforts to enhance their capacity for gene delivery had focused on their capsids. However, efforts are increasingly shifting towards improving the viral replication protein, Rep78. We discovered that Rep78 and its shorter isoform Rep52 contain a strictly C-terminal sequence motif, DDx3EQ, conserved in most dependoparvoviruses. The motif is highly negatively charged and devoid of prolines. Its wide conservation suggests that it is required for the life cycle of dependoparvoviruses. Despite its short length, the motif's strictly C-terminal position has the potential to endow it with a high recognition specificity. A candidate target of the DDx3EQ motif might be the DNA-binding interface of the origin-binding domain of Rep78, which is highly positively charged. Published studies suggest that this motif is not required for recombinant AAV production, but that substitutions within it might improve production.</p>","PeriodicalId":49328,"journal":{"name":"Viruses-Basel","volume":"16 11","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11598897/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Adeno-Associated Virus Replication Protein Rep78 Contains a Strictly C-Terminal Sequence Motif Conserved Across Dependoparvoviruses.\",\"authors\":\"David G Karlin\",\"doi\":\"10.3390/v16111760\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Adeno-Associated Viruses (AAVs, genus <i>Dependoparvovirus</i>) are the leading gene therapy vector. Until recently, efforts to enhance their capacity for gene delivery had focused on their capsids. However, efforts are increasingly shifting towards improving the viral replication protein, Rep78. We discovered that Rep78 and its shorter isoform Rep52 contain a strictly C-terminal sequence motif, DDx3EQ, conserved in most dependoparvoviruses. The motif is highly negatively charged and devoid of prolines. Its wide conservation suggests that it is required for the life cycle of dependoparvoviruses. Despite its short length, the motif's strictly C-terminal position has the potential to endow it with a high recognition specificity. A candidate target of the DDx3EQ motif might be the DNA-binding interface of the origin-binding domain of Rep78, which is highly positively charged. Published studies suggest that this motif is not required for recombinant AAV production, but that substitutions within it might improve production.</p>\",\"PeriodicalId\":49328,\"journal\":{\"name\":\"Viruses-Basel\",\"volume\":\"16 11\",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-11-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11598897/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Viruses-Basel\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3390/v16111760\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"VIROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Viruses-Basel","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/v16111760","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
腺相关病毒(AAV,隶属于依赖性巴病毒属)是基因治疗的主要载体。直到最近,提高其基因递送能力的努力都集中在其囊壳上。然而,人们正越来越多地转向改进病毒复制蛋白 Rep78。我们发现,Rep78 及其较短的异构体 Rep52 含有一个严格的 C 端序列基序 DDx3EQ,这在大多数隶属病毒中都是保守的。该基序带高负电荷,不含脯氨酸。它的广泛保守性表明,隶属病毒的生命周期需要它。尽管它的长度很短,但其严格的 C 端位置有可能赋予它很高的识别特异性。DDx3EQ 主题的一个候选目标可能是 Rep78 起源结合域的 DNA 结合界面,该界面带高正电荷。已发表的研究表明,重组 AAV 的生产并不需要该基序,但该基序的替代可能会提高产量。
The Adeno-Associated Virus Replication Protein Rep78 Contains a Strictly C-Terminal Sequence Motif Conserved Across Dependoparvoviruses.
Adeno-Associated Viruses (AAVs, genus Dependoparvovirus) are the leading gene therapy vector. Until recently, efforts to enhance their capacity for gene delivery had focused on their capsids. However, efforts are increasingly shifting towards improving the viral replication protein, Rep78. We discovered that Rep78 and its shorter isoform Rep52 contain a strictly C-terminal sequence motif, DDx3EQ, conserved in most dependoparvoviruses. The motif is highly negatively charged and devoid of prolines. Its wide conservation suggests that it is required for the life cycle of dependoparvoviruses. Despite its short length, the motif's strictly C-terminal position has the potential to endow it with a high recognition specificity. A candidate target of the DDx3EQ motif might be the DNA-binding interface of the origin-binding domain of Rep78, which is highly positively charged. Published studies suggest that this motif is not required for recombinant AAV production, but that substitutions within it might improve production.
期刊介绍:
Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.