内在无序可能驱动 PROS1 和 MERTK 在葡萄膜黑色素瘤中的相互作用。
Intrinsic disorder may drive the interaction of PROS1 and MERTK in uveal melanoma.
机构信息
Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
出版信息
Int J Biol Macromol. 2023 Oct 1;250:126027. doi: 10.1016/j.ijbiomac.2023.126027. Epub 2023 Jul 26.
BACKGROUND
Class 2 uveal melanomas are associated with the inactivation of the BRCA1 ((breast cancer type 1 susceptibility protein)-associated protein 1 (BAP1)) gene. Inactivation of BAP1 promotes the upregulation of vitamin K-dependent protein S (PROS1), which interacts with the tyrosine-protein kinase Mer (MERTK) receptor on M2 macrophages to induce an immunosuppressive environment.
METHODS
We simulated the interaction of PROS1 with MERTK with ColabFold. We evaluated PROS1 and MERTK for the presence of intrinsically disordered protein regions (IDPRs) and disorder-to-order (DOT) regions to understand their protein-protein interaction (PPI). We first evaluated the structure of each protein with AlphaFold. We then analyzed specific sequence-based features of the PROS1 and MERTK with a suite of bioinformatics tools.
RESULTS
With high-resolution, moderate confidence, we successfully modeled the interaction between PROS1 and MERTK (predicted local distance difference test score (pDLLT) = 70.68). Our structural analysis qualitatively demonstrated IDPRs (i.e., spaghetti-like entities) in PROS1 and MERK. PROS1 was 23.37 % disordered, and MERTK was 23.09 % disordered, classifying them as moderately disordered and flexible proteins. PROS1 was significantly enriched in cysteine, the most order-promoting residue (p-value <0.05). Our IUPred analysis demonstrated that there are two disorder-to-order transition (DOT) regions in PROS1. MERTK was significantly enriched in proline, the most disorder-promoting residue (p-value <0.05), but did not contain DOT regions. Our STRING analysis demonstrated that the PPI network between PROS1 and MERTK is more complex than their assumed one-to-one binding (p-value <2.0 × 10).
CONCLUSION
Our findings present a novel prediction for the interaction between PROS1 and MERTK. Our findings show that PROS1 and MERTK contain elements of intrinsic disorder. PROS1 has two DOT regions that are attractive immunotherapy targets. We recommend that IDPRs and DOT regions found in PROS1 and MERTK should be considered when developing immunotherapies targeting this PPI.
背景
2 类葡萄膜黑色素瘤与 BRCA1（乳腺癌 1 型易感蛋白）相关蛋白 1（BAP1）基因失活有关。BAP1 的失活促进了维生素 K 依赖性蛋白 S（PROS1）的上调，PROS1 与 M2 巨噬细胞上的酪氨酸蛋白激酶 Mer（MERTK）受体相互作用，诱导免疫抑制环境。
方法
我们使用 ColabFold 模拟了 PROS1 与 MERTK 的相互作用。我们评估了 PROS1 和 MERTK 是否存在无规卷曲蛋白区域（IDPRs）和无序到有序（DOT）区域，以了解它们的蛋白质-蛋白质相互作用（PPI）。我们首先使用 AlphaFold 评估了每种蛋白质的结构。然后，我们使用一系列生物信息学工具分析了 PROS1 和 MERTK 的特定序列特征。
结果
我们成功地以高分辨率、中等置信度模拟了 PROS1 和 MERTK 之间的相互作用（预测局部距离差异测试得分（pDLLT）=70.68）。我们的结构分析定性地证明了 PROS1 和 MERK 中的 IDPRs（即意大利面条状实体）。PROS1 无序度为 23.37%，MERTK 无序度为 23.09%，被归类为中度无序和灵活的蛋白质。PROS1 中半胱氨酸显著富集，半胱氨酸是最促进有序的残基（p 值<0.05）。我们的 IUPred 分析表明，PROS1 中有两个无序到有序的转变（DOT）区域。MERTK 脯氨酸显著富集，脯氨酸是最促进无序的残基（p 值<0.05），但不含 DOT 区域。我们的 STRING 分析表明，PROS1 和 MERTK 之间的 PPI 网络比它们假设的一对一结合更为复杂（p 值<2.0×10）。
结论
我们的研究结果提出了 PROS1 和 MERTK 相互作用的新预测。我们的研究结果表明，PROS1 和 MERTK 包含内在无序的元素。PROS1 有两个 DOT 区域，是有吸引力的免疫治疗靶点。我们建议在开发针对该 PPI 的免疫疗法时，应考虑 PROS1 和 MERTK 中发现的 IDPRs 和 DOT 区域。
Zotero 插件