一种MHC-I/TAPBPR结中间体的冷EM结构揭示了抗原校对的机制
bioRxiv : the preprint server for biology
|August 30, 2024
概括
研究人员发现了抗原编辑复合体如何校对适应性免疫的. 这种机制涉及结槽内的特定相互作用,这对于T细胞识别和疫苗开发至关重要.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 分子生物学分子生物学
背景情况:
- 一级主要基因相容性复合体 (MHC-I) 蛋白向CD8+T细胞呈现,这是适应性免疫的一个关键步骤.
- 像塔帕辛和TAPBPR这样的伴侣对于从庞大的细胞内池中选择免疫性来说至关重要.
- MHC-I和相互作用的短暂性质已经掩盖了精确的抗原校对机制.
研究的目的:
- 通过MHC-I编辑复合体阐明抗原校对的分子机制.
- 确定与诱结合的人类抗原编辑复合物的高分辨率结构.
- 研究临床相关的MHC-I异形体中细胞表面交换的潜力.
主要方法:
- 使用了一种高保真性TAPBPR变体,并对MHC-I.I.进行了形状稳定.
- 使用低温电子显微镜 (cryo-EM) 在3.0 Å分辨率下确定溶液结构.
- 在多个人类MHC-I全态体中证明了细胞表面交换.
主要成果:
- 通过MHC-I结槽和 anchors (P2/P3) 之间的短暂相互作用来调解暴露的抗原校对.
- 识别了保存的MHC-I残留物,这些残留物通过脊柱聚焦接触来稳定传入的.
- 在细胞表面展示了强大的交换,用于各种人类MHC-I异形体,使用高保真性伴侣.
结论:
- 该研究为MHC-I抗原校对提供了详细的结构和机制理解.
- 这些发现澄清了在编辑过程中如何识别和稳定特定的基.
- 在疫苗设计和T细胞查中,证明了高保真性护手对操纵T细胞表位选择的潜力.
相关概念视频
Antigen Processing Pathways
960
MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
MHC Class I: Presenting Endogenous...
MHC Class I: Presenting Endogenous...
960
Improving Translational Accuracy
9.4K
Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
9.4K
Cryo-electron Microscopy
3.3K
Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...
3.3K
Antigens Involved in Adaptive Immunity
476
An antigen is any substance the immune system identifies as foreign and potentially harmful to the body, prompting an immune response. Antigens have two functional properties: immunogenicity and reactivity. Immunogenicity is the ability of an antigen to stimulate a specific immune response. At the same time, reactivity describes the antigen's ability to react with the cells and antibodies produced in response to it.
Complete Antigens
Complete antigens possess both immunogenicity and...
Complete Antigens
Complete antigens possess both immunogenicity and...
476
Proofreading
6.2K
Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template DNA strand. DNA polymerase has a higher affinity to add the correct base and ensures fidelity during DNA replication. Furthermore, it exhibits proofreading activity during replication, using an exonuclease domain that cuts off incorrect nucleotides from the nascent DNA strand.
Errors During Replication are Corrected by the DNA Polymerase...
Errors During Replication are Corrected by the DNA Polymerase...
6.2K
Protein Folding Quality Check in the RER
3.7K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.7K


