PRAME（全称：在黑色素瘤中特异性表达的抗原）蛋白已被证明是一种独立的生物标志物，与一级脉络膜黑色素瘤（UM）的转移风险增加有关。内源性无序蛋白和蛋白区域（IDPs / IDPRs）是指没有明确定义的三维结构，与肿瘤发生发展有关的蛋白质。本研究旨在评估PRAME中的内在无序性，并探讨这些无结构区域在PRAME（ +）一级UM中的作用。进行了一项生物信息学研究以表征PRAME对内在无序的趋势。我们首先使用AlphaFold工具定性评估PRAME的蛋白质结构。然后，我们使用了组成分析分析器和一组逐残基内在无序性预测器来量化内在无序性。无序蛋白质预测数据库（D2P2）平台、IUPred、FuzDrop、fIDPnn、AUCpred、SPOT-Disorder2和metapredict V2等工具帮助我们评估PRAME的潜在功能无序性。此外，我们还使用“搜索与检索相互作用基因”（STRING）工具来分析PRAME与其他蛋白质的潜在相互作用结构。我们的结构分析显示，PRAME包含内在无序蛋白区域（IDPRs），这些区域无结构且具有可塑性。我们发现PRAME包含丰富的丝氨酸（p值<0.05），这是一种促使无序性的氨基酸。通过六个逐残基内在无序性预测器的分析，我们发现PRAME的平均无序性得分为16.49％（即中度无序）。我们的IUPred分析揭示了PRAME蛋白中的无序-有序转变（DOT）区域位于蛋白质的C-末端（残基475-509）。D2P2平台预测了约140和175之间的一个区域高度富集了翻译后修饰（PTMs）。FuzDrop预测PRAME的PTM热点是一个凝滴促进区域和一个聚集热点。最后，我们使用STRING工具的分析显示，PRAME与其他蛋白质的相互作用显著超过了与随机选择的相同大小的蛋白质的预期相互作用，具有与84个不同伙伴蛋白质的相互作用能力（STRING分析结果：p值<1.0×10-16；模型置信度：0.400）。我们的研究表明PRAME在一级UM的背景下具有与其功能可能相关的IDPRs。功能性区域（即DOT区域，PTM位点，凝滴促进区域和聚集热点）局限于高度无序的区域。PRAME具有复杂的蛋白-蛋白互作（PPI）网络，这可能是多肽无结构特征的次要效应。我们的发现有助于我们对UM的理解，并暗示PRAME中的IDPRs和DOT区域可能成为开发针对该侵袭性癌症的新治疗方法的靶点。视频摘要。© 2023 BioMed Central Ltd.和Springer Nature的一部分。

The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM.A bioinformatics study to characterize PRAME's propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the protein structure of PRAME. Then we used the Compositional Profiler and a set of per-residue intrinsic disorder predictors to quantify the intrinsic disorder. The Database of Disordered Protein Prediction (D2P2) platform, IUPred, FuzDrop, fIDPnn, AUCpred, SPOT-Disorder2, and metapredict V2 allowed us to evaluate the potential functional disorder of PRAME. Additionally, we used the Search Tool for the Retrieval of Interacting Genes (STRING) to analyze PRAME's potential interactions with other proteins.Our structural analysis showed that PRAME contains intrinsically disordered protein regions (IDPRs), which are structureless and flexible. We found that PRAME is significantly enriched with serine (p-value < 0.05), a disorder-promoting amino acid. PRAME was found to have an average disorder score of 16.49% (i.e., moderately disordered) across six per-residue intrinsic disorder predictors. Our IUPred analysis revealed the presence of disorder-to-order transition (DOT) regions in PRAME near the C-terminus of the protein (residues 475-509). The D2P2 platform predicted a region from approximately 140 and 175 to be highly concentrated with post-translational modifications (PTMs). FuzDrop predicted the PTM hot spot of PRAME to be a droplet-promoting region and an aggregation hotspot. Finally, our analysis using the STRING tool revealed that PRAME has significantly more interactions with other proteins than expected for randomly selected proteins of the same size, with the ability to interact with 84 different partners (STRING analysis result: p-value < 1.0 × 10-16; model confidence: 0.400).Our study revealed that PRAME has IDPRs that are possibly linked to its functionality in the context of Class 1 UM. The regions of functionality (i.e., DOT regions, PTM sites, droplet-promoting regions, and aggregation hotspots) are localized to regions of high levels of disorder. PRAME has a complex protein-protein interaction (PPI) network that may be secondary to the structureless features of the polypeptide. Our findings contribute to our understanding of UM and suggest that IDPRs and DOT regions in PRAME may be targeted in developing new therapies for this aggressive cancer. Video Abstract.© 2023. BioMed Central Ltd., part of Springer Nature.