The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome.
The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome.
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作者：
慢性肺部疾病，如囊性纤维化、慢性支气管炎和哮喘，以高分泌和粘液清除不良为特征，与预后和死亡率有关。粘液的生物物理性质与其分子组成之间的关系知之甚少。粘蛋白MUC5B和MUC5AC传统上被认为产生了呼吸道粘液特有的生物物理特性。然而，数百种球状蛋白对粘液的生物物理性质的贡献尚不清楚。大约三分之一的粘液蛋白质组由以呼吸道粘蛋白为中心的不同的多蛋白复合体组成。这些复合体构成一个离散的实体，我们称之为“粘蛋白相互作用体”。这些数据表明，虽然这些蛋白质中的大多数通过静电和弱相互作用与粘蛋白相互作用，但也有一些通过非常强的疏水和/或共价相互作用相互作用。使用干扰蛋白质相互作用的试剂，可以拆解复合体，粘液流变学可以显著改变。以MUC5B-谷胱甘肽S转移酶(GST)和MUC5B-Galectin-3为代表，我们提供了单独的粘蛋白蛋白相互作用可以改变粘液的生物物理性质并调节蛋白质的生物学功能的证据。我们认为粘液的关键机械和生物活性功能依赖于粘蛋白和球状蛋白之间的动态相互作用。这些观察结果挑战了粘蛋白是赋予粘液生物物理性质的唯一分子的范式。这些观察结果可能最终导致对该系统的更好理解，并指导制定使用更好的治疗剂进行更有效干预的策略。
Chronic lung diseases such as cystic fibrosis, chronic bronchitis and asthma, are characterized by hypersecretion and poor clearance of mucus, which are associated with poor prognosis and mortality. Little is known about the relationship between the biophysical properties of mucus and its molecular composition. The mucins MUC5B and MUC5AC are traditionally believed to generate the characteristic biophysical properties of airway mucus. However, the contribution of hundreds of globular proteins to the biophysical properties of mucus is not clear. Approximately one-third of the total mucus proteome comprises distinct, multi-protein complexes centered around airway mucins. These complexes constitute a discrete entity we call the “mucin interactome”. The data suggest that while the majority of these proteins interact with mucins via electrostatic and weak interactions, some interact through very strong hydrophobic and/or covalent interactions. Using reagents that interfere with protein-protein interactions, the complexes can be disassembled, and mucus rheology can be dramatically altered. Using MUC5B-glutathione S-transferase (GST) and MUC5B-galectin-3 as a representative of these interactions, we provide evidence that individual mucin protein interactions can alter the biophysical properties of mucus and modulate the biological function of the protein. We propose that the key mechano- and bio-active functions of mucus depend on the dynamic interactions between mucins and globular proteins. These observations challenge the paradigm that mucins are the only molecules that confer biophysical properties of mucus. These observations may ultimately lead to a greater understanding of the system and guide the development of strategies for more effective interventions using better therapeutic agents.
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影响因子：
8
作者：
通讯作者：
--
DOI：
10.1126/science.1223012
发表时间：
2012-08-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Button B;Cai LH;Ehre C;Kesimer M;Hill DB;Sheehan JK;Boucher RC;Rubinstein M
通讯作者：
Rubinstein M
DOI：
10.1152/ajplung.90388.2008
发表时间：
2009-01
影响因子：
4.9
作者：
Kesimer, Mehmet;Kirkham, Sara;Pickles, Raymond J.;Henderson, Ashley G.;Alexis, Neil E.;DeMaria, Genevieve;Knight, David;Thornton, David J.;Sheehan, John K.
通讯作者：
Sheehan, John K.
DOI：
10.1007/978-1-61779-513-8_4
发表时间：
2012-01-01
期刊：
MUCINS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Kesimer, Mehmet;Sheehan, John K.
通讯作者：
Sheehan, John K.
影响因子：
4.4
作者：
Cao, Rui;Wang, T. Tiffany;Kesimer, Mehmet
通讯作者：
Kesimer, Mehmet