{"id":429,"title":"Allosteric disulfide control of ligand binding and endocytosis of KIR2DL4, the natural killer cell receptor for HLA-G","title_zh":"变构二硫键调控 KIR2DL4（HLA-G 的 NK 细胞受体）的配体结合与内吞","url":"https://pubmed.ncbi.nlm.nih.gov/42867135","doi":"10.7554/elife.111018","pmid":"42867135","journal":"Elife","kind":"paper","lang":"en","published_at":"2026-10-13T00:00:00+00:00","fetched_at":"2026-11-08T03:44:13+00:00","authors":["Rajagopalan S","Chiu J","Chaurasia P","Lu J","Mastorakos GM","Majumder S","Nolan KT","Petersen J","Adams EJ","Sun PD","Rossjohn J","Hogg PJ","Long EO"],"primary_topic":"repro-immunology","topics":[{"slug":"repro-immunology","score":8.0,"hits":["hla","hla-g","natural killer cell"]},{"slug":"endometrium","score":2.0,"hits":["placental","trophoblast"]},{"slug":"omics-methods","score":1.0,"hits":["mass spectrometry"]}],"topic_score":8.0,"preference_score":0.0,"preference_labels":[],"llm_score":74.0,"final_score":80.0,"score_dims":{"novelty":82,"rigor":80,"impact":68,"relevance":60,"translation":38},"recommend_reason":"首次以变构二硫键（Cys10-Cys28↔Cys28-Cys74）与 PDI 还原机制解释 KIR2DL4 的 HLA-G 结合开关，为母胎界面 NK 细胞识别提供清晰分子模型；机制扎实、证据链完整，但与 ART 临床操作距离较远，属基础生殖免疫读物。","keywords":["KIR2DL4","HLA-G","变构二硫键","蛋白二硫键异构酶(PDI)","自然杀伤细胞","母胎界面"],"selected":1,"story_id":411,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"elife","journal_tier":"general-top","journal_if":6.4,"is_mock":false,"summary_zh":"该研究探讨人 NK 细胞受体 KIR2DL4 识别胎儿滋养层细胞特异性 HLA-G 的结构基础。随机突变筛选发现，KIR2DL4 第一免疫球蛋白结构域中的三个半胱氨酸调控其内吞及 HLA-G 摄取；其中非典型的 Cys10-Cys28 二硫键为可变构二硫键，可转换为经典的 Cys28-Cys74 键，质谱证实人细胞中两种状态共存。体外实验显示 PDI 可还原 Cys10-Cys28 键，抑制 PDI 则阻断 NK 细胞对 HLA-G 的摄取。Cys10-Cys28 构型突变体自发内吞但不结合 HLA-G，而 Cys28-Cys74 构型定位于质膜并可内化可溶性 HLA-G；纯化的 Cys10Leu 突变体以微摩尔亲和力、肽依赖性方式结合 HLA-G。结论：变构二硫键转换控制 KIR2DL4 从无活性态向 HLA-G 结合态的转变，进而调节其转运与促胎盘发育的功能反应。","summary":"Human Leukocyte Antigen (HLA)-G is selectively expressed by fetal trophoblast cells that encounter maternal natural killer (NK) cells early in pregnancy. In response to HLA-G, the endosomal NK cell receptor KIR2DL4 induces a transcriptional program to support placental development. Structural features of KIR2DL4 that control HLA-G binding and endocytosis are unclear. Random mutagenesis revealed that three cysteines in the first immunoglobulin domain of KIR2DL4 regulate endocytosis and uptake of HLA-G. The atypical Cys10-Cys28 disulfide bond in the KIR2DL4 structure is an allosteric disulfide with potential to switch to a conventional Cys28-Cys74 bond. KIR2DL4 in human cells exists in both disulfide-bonded states, as shown by mass spectrometry analysis. The Cys10-Cys28 bond in a Cys74Ser KIR2DL4 mutant was reduced by protein disulfide isomerase (PDI) in vitro. Inhibition of PDI prevented HLA-G uptake by KIR2DL4 in NK cells. Mutants in the Cys10-Cys28 configuration endocytosed spontaneously but did not bind HLA-G. Conversely, KIR2DL4 with a Cys28-Cys74 bond was detectable at the plasma membrane and internalized soluble HLA-G. A purified Cys10Leu KIR2DL4 mutant bound HLA-G with micromolar affinity in a peptide-dependent manner. Thus, allosteric disulfide-mediated conversion from an inactive to an HLA-G binding form regulates KIR2DL4 trafficking and a functional response that promotes fetal development.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}