Assembly Mechanism of Mucin and von Willebrand Factor Polymers

Abstract

Summary 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.

Conformation of the von Willebrand factor/factor VIII complex in quasi-static flow

“…One example is the mucin family of glycoproteins, which like VWF, consist of ∼0.5 MDa protomers with molecular weights extending to ∼20 MDa ( 49 ) and display MHKS relationships consistent with a random coil conformation ( 50 ). Like VWF, mucins are heavily O-glycosylated and contain a cysteine-rich domain homologous to the VWF C and D domains, indicating a common evolutionary origin of the flexibility of these proteins ( 51 ).…”

The IgGFc-binding protein FCGBP is secreted with all GDPH sequences cleaved but maintained by interfragment disulfide bonds

“…S3B). There is structural information of vWD domains obtained from X-ray crystallography and cryo-EM studies of the vWF and MUC2 respectively (30,31). Using the vWF structure, the FCGBP vWD1 domain structure was modelled to obtain further information of the potential Cys involved in the stabilization of the GDPH cleaved protein (Fig 4A).…”

The Relationship between Mucins and Ulcerative Colitis: A Systematic Review

“…Secreted gel forming mucins such as MUC2 have an oligomeric structure which appears as a layered network of monomers bonded together through disulphide bridges whereas secreted soluble mucins such as MUC7 are much smaller and appear monomeric [ 2 , 10 , 16 ]. The gel forming secreted mucins can be distinguished by their cysteine rich domains and their ability to form von Willebrand factor like C and D domains [ 4 , 10 , 17 ]. However, the secreted soluble mucins (MUC7, MUC8, MUC9) are not as well characterised as secreted gel forming mucins.…”