Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
FASEB J. 2020 Feb;34(2):1939-1957. doi: 10.1096/fj.201901898RR. Epub 2020 Jan 5.
Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O- and N- glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs). This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins.
许多黏蛋白家族成员在进化上是保守的，并且在各种良性和恶性病理中经常异常表达和糖基化，导致肿瘤侵袭、转移和免疫逃逸。黏蛋白的大尺寸和广泛糖基化给使用传统方法（包括晶体学）研究黏蛋白结构带来了挑战。我们提出假设，即黏蛋白的多功能性可能归因于存在固有无序区域（IDR），这些 IDR 提供了动态性和灵活性，并且 IDR 提供了潜在的治疗靶点。本文基于 IDR、翻译后修饰（PTM）以及对其互作组的潜在影响，研究了黏蛋白结构和功能之间的联系。我们使用基于序列的生物信息学工具观察到，黏蛋白被预测为中度（20%-40%）到高度（>40%）无序，并且许多保守的黏蛋白结构域可能是无序的。磷酸化位点与黏蛋白序列中的 IDR 重叠。此外，串联重复区域中大多数预测的 O-和 N-糖基化位点发生在 IDR 内，这些 IDR 包含大量功能基序，即分子识别特征（MoRF），这些特征直接影响蛋白质-蛋白质相互作用（PPIs）。这项研究提供了一个新的视角，并深入了解了黏蛋白的复杂性和动态性质。
