Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea; College of Pharmacy, Chonnam National University, Kwangju, Republic of Korea.
Animal Genome & Bioinformatics Division, National Institute of Animal Science, RDA, Wanju, Republic of Korea.
Int J Biol Macromol. 2021 May 1;178:514-526. doi: 10.1016/j.ijbiomac.2021.02.196. Epub 2021 Mar 1.
The binding mode to TAP (i.e., the peptide transporter associated with antigen processing) from a viral peptide thus far has been unknown in the field of antiviral immunity, but an interfering mode from a virus-encoded TAP inhibitor has been well documented with respect to blocking the TAP function. In the current study, we predicted the structure of the pig TAP transporter and its inhibition complex by the small viral protein ICP47 of the herpes simplex virus (HSV) encoded by the TAP inhibitor to exploit inhibition of the TAP transporter as the host's immune evasion strategy. We found that the hot spots (residues Leu5, Tyr22, and Leu51) on the ICP47 inhibitor interface tended to prevail over the favored Leu and Tyr, which contributed to significant functional binding at the C-termini recognition principle of the TAP. We further characterized the specificity determinants of the peptide transporter from the pig TAP by the ICP47 inhibitor effects and multidrug TmrAB transporter from the Thermus thermophillus and its immunity regarding its structural homolog of the pig TAP. The specialized structure-function relationship from the pig TAP exporter could provide insight into substrate specificity of the unique immunological properties from the host organism. The TAP disarming capacity from all five viral inhibitors (i.e., the five virus-encoded TAP inhibitors of ICP47, UL49.5, U6, BNLF2a, and CPXV012 proteins) was linked to the infiltration of the TAP functional structure in an unstable conformation and the mounting susceptibility caused by the host's TAP polymorphism. It is anticipated that the functional characterization of the pig TAP transporter based on the pig genomic variants will lead to additional insights into the genotype and single nucleotide polymorphism (SNP) in relation to antiviral resistance and disease susceptibility.
针对抗病毒免疫领域中 TAP（即与抗原加工相关的肽转运体）的结合模式目前仍不清楚，但病毒编码的 TAP 抑制剂的干扰模式已被充分记录，该模式可通过阻断 TAP 功能来抑制病毒。在本研究中，我们通过单纯疱疹病毒（HSV）编码的 TAP 抑制剂的病毒小蛋白 ICP47 预测了猪 TAP 转运体及其抑制复合物的结构，以利用 TAP 转运体的抑制作用作为宿主的免疫逃避策略。我们发现 ICP47 抑制剂界面上的热点（残基 Leu5、Tyr22 和 Leu51）倾向于占据有利的 Leu 和 Tyr，这有助于在 TAP 的 C 末端识别原理上进行重要的功能结合。我们进一步通过 ICP47 抑制剂效应和来自 Thermus thermophillus 的多药 TmrAB 转运体及其对猪 TAP 结构同源物的免疫作用，对猪 TAP 的肽转运体的特异性决定因素进行了表征。猪 TAP 外排泵的特殊结构-功能关系可以深入了解宿主生物体独特免疫特性的底物特异性。所有五种病毒抑制剂（即 ICP47、UL49.5、U6、BNLF2a 和 CPXV012 蛋白的五种病毒编码 TAP 抑制剂）的 TAP 解除武装能力与 TAP 功能结构的渗透有关不稳定构象和宿主 TAP 多态性引起的易感性增加。预计基于猪基因组变异对猪 TAP 转运体的功能特征进行研究将有助于进一步了解与抗病毒抗性和疾病易感性相关的基因型和单核苷酸多态性（SNP）。
