Assembly Mechanism of Mucin and von Willebrand Factor Polymers.
Assembly Mechanism of Mucin and von Willebrand Factor Polymers.
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DOI：
10.1016/j.cell.2020.09.021
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发表时间：
2020-10-29
期刊：
影响因子：
64.5
通讯作者：
Fass D
中科院分区：
文献类型：
--
作者：
Javitt G;Khmelnitsky L;Albert L;Bigman LS;Elad N;Morgenstern D;Ilani T;Levy Y;Diskin R;Fass D
呼吸道和肠道因吸入空气和食物而受到物理和生物危害。同样，血管系统也受到炎症和创伤的威胁。粘蛋白糖蛋白和相关的血管性血友病因子在这些不同的系统中保护着脆弱的细胞层。结肠粘蛋白还为肠道微生物群提供住所和饲料。在这里，我们提出了肠粘蛋白MUC2的综合结构分析。我们的发现揭示了一种共同的机制，即负责凝血、粘膜纤毛清除和肠粘膜屏障的复杂大分子形成保护性聚合物和水凝胶。具体来说，低温电子显微镜和晶体结构显示了富二硫桥和ph可调界面如何控制内质网和高尔基体中的连续组装步骤。值得注意的是，密集的o糖基化粘蛋白结构域在MUC2中发挥组织作用。黏蛋白的组装机制及其对止血的适应性为合理操纵屏障功能和凝血提供了基础。粘蛋白糖蛋白在高尔基pH下的超分子组装促进聚合物形成o -糖基化区域帮助协调粘蛋白组装CysD结构域具有新的折叠、钙结合基元以及在粘蛋白组装中的作用粘蛋白和血管性血友病因子共享一种形成线性聚合物的机制Javitt等人从分子上描述了粘蛋白糖蛋白和血管性血友病因子复合物大分子如何在肺、肠粘膜屏障、凝血——利用一种共同的机制形成聚合物和水凝胶，保护呼吸道、肠道和脉管系统。
The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation. Mucin glycoprotein supramolecular assembly at Golgi pH promotes polymer formation O-glycosylated regions help orchestrate mucin assembly CysD domains have a novel fold, calcium binding motifs, and a role in mucin assembly Mucins and von Willebrand factor share a mechanism to form linear polymers Javitt et al. describe molecularly how mucin glycoproteins and von Willebrand factor—complex macromolecules responsible for mucociliary clearance in the lung, the intestinal mucosal barrier, and blood clotting—use a shared mechanism to form polymers and hydrogels that protect the respiratory tract, intestinal tract, and vasculature.
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富含半胱氨酸残基的粘蛋白结构域的递送增强了肠粘膜。
影响因子：
4.6
作者：
Gouyer V;Dubuquoy L;Robbe-Masselot C;Neut C;Singer E;Plet S;Geboes K;Desreumaux P;Gottrand F;Desseyn JL
通讯作者：
Desseyn JL
影响因子：
3.6
作者：
Lathem, WW;Grys, TE;Welch, RA
通讯作者：
Welch, RA
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3.7
作者：
Guo, XueLiang;Pace, Rhonda G.;Knowles, Michael R.
通讯作者：
Knowles, Michael R.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC