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SARS-CoV PBM 与细胞 PDZ 结构域相互作用导致病毒毒力。

Interaction between SARS-CoV PBM and Cellular PDZ Domains Leading to Virus Virulence.

机构信息

Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.

Scientific Computing Service, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.

出版信息

Viruses. 2024 Jul 29;16(8):1214. doi: 10.3390/v16081214.

DOI:10.3390/v16081214
PMID:39205188
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11359647/
Abstract

The interaction between SARS-CoV PDZ-binding motifs (PBMs) and cellular PDZs is responsible for virus virulence. The PBM sequence present in the 3a and envelope (E) proteins of SARS-CoV can potentially bind to over 400 cellular proteins containing PDZ domains. The role of SARS-CoV 3a and E proteins was studied. SARS-CoVs, in which 3a-PBM and E-PMB have been deleted (3a-PBM-/E-PBM-), reduced their titer around one logarithmic unit but still were viable. In addition, the absence of the E-PBM and the replacement of 3a-PBM with that of E did not allow the rescue of SARS-CoV. E protein PBM was necessary for virulence, activating p38-MAPK through the interaction with Syntenin-1 PDZ domain. However, the presence or absence of the homologous motif in the 3a protein, which does not bind to Syntenin-1, did not affect virus pathogenicity. Mutagenesis analysis and in silico modeling were performed to study the extension of the PBM of the SARS-CoV E protein. Alanine and glycine scanning was performed revealing a pair of amino acids necessary for optimum virus replication. The binding of E protein with the PDZ2 domain of the Syntenin-1 homodimer induced conformational changes in both PDZ domains 1 and 2 of the dimer.

摘要

SARS-CoV PDZ 结合基序（PBM）与细胞 PDZ 的相互作用是病毒毒力的基础。SARS-CoV 的 3a 和包膜（E）蛋白中存在的 PBM 序列可以潜在地与含有 PDZ 结构域的 400 多种细胞蛋白结合。研究了 SARS-CoV 3a 和 E 蛋白的作用。3a-PBM 和 E-PMB 缺失的 SARS-CoV（3a-PBM-/E-PBM-）滴度降低了一个对数单位，但仍具有活力。此外，缺乏 E-PBM 并用 E 的 PBM 取代也不能拯救 SARS-CoV。E 蛋白 PBM 对于毒力是必需的，通过与 Syntenin-1 PDZ 结构域相互作用激活 p38-MAPK。然而，3a 蛋白中同源基序的存在或不存在（不与 Syntenin-1 结合）并不影响病毒的致病性。进行了突变分析和计算机建模，以研究 SARS-CoV E 蛋白 PBM 的扩展。进行了丙氨酸和甘氨酸扫描，揭示了一对对病毒复制最优化至关重要的氨基酸。E 蛋白与 Syntenin-1 同源二聚体的 PDZ2 结构域的结合诱导二聚体的 PDZ1 和 PDZ2 结构域的构象变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/d1c59584bc9a/viruses-16-01214-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/8c436e051844/viruses-16-01214-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/f77dabe43dad/viruses-16-01214-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/a99e46810cf1/viruses-16-01214-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/66575d824738/viruses-16-01214-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/b1cda3f6484a/viruses-16-01214-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/11313fd85923/viruses-16-01214-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/845a071739da/viruses-16-01214-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/0c98a3594226/viruses-16-01214-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/d1c59584bc9a/viruses-16-01214-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/8c436e051844/viruses-16-01214-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/f77dabe43dad/viruses-16-01214-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/a99e46810cf1/viruses-16-01214-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/66575d824738/viruses-16-01214-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/b1cda3f6484a/viruses-16-01214-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/11313fd85923/viruses-16-01214-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/845a071739da/viruses-16-01214-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/0c98a3594226/viruses-16-01214-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce37/11359647/d1c59584bc9a/viruses-16-01214-g009.jpg

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