Perspectives on mucus properties and formation--lessons from the biochemical world

Abstract

Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the mucin granule it is organized by an amino-terminal concatenated ring platform formed at high calcium and low pH. This packing allows an ordered release and a normal mucin expansion when calcium is removed and pH increased by bicarbonate. This process is defective in the absence of cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate transport. The expanded secreted mucin is suggested to be self-organizing by properties inherited in the MUC2 mucin and by proteolytic processes.

Figure 1.

A schematic view of the MUC2 mucin (top). The amino-terminal von Willebrand D1, D2, and D3 (VWD1–3) domains comprising the first 1200 amino acids are given as a blue dot. The two mucin domains are green. The CysD domains are red (only one of the two is shown). The carboxy-terminal 980 amino acids, including the von Willebrand D4 (VWD4) and the cysteine-knot domains are given in black. (A) Disulfide-bonded dimeric carboxy terminus as formed in the endoplasmic reticulum. (B) Disulfide-bonded trimeric amino terminus as formed in the secretory vesicles. (C) Nonreducible covalent bond formed in the late secretory pathway. (D) CysD domains form noncovalent dimeric complexes. (E) The autocatalytic cleavage at the GD/PH bond (between aspartate and proline in the sequence glycine-aspartate-proline-histidine) in the carboxy-terminal von Willebrand D4 domain generates a new carboxy terminus with an internal anhydride that can cross-link MUC2. (F) FCGBP has 11 von Willebrand D domains (VWD) with a cleavage GD/PH site and two without. As for MUC2, the GD/PH bond is cleaved and will cross-link, for example, MUC2.

Figure 2.

Schematic model of the packed assembled MUC2 polymer as found in the mucin granules of the goblet cells. (A) Side view, and (B) bottom view. The MUC2 mucin is shown in a 2D projection. Colors as in Figure 1.

Figure 3.

Schematic model of an early stage of unpacking of the assembled MUC2. (A) Side view, and (B) top view. The MUC2 mucin is shown in a 2D projection. Colors as in Figure 1.

Figure 4.

Model of expected organization of the stratified inner mucus layer of colon. Schematic drawing of the fully unfolded secreted MUC2 polymer netlike network (A) formed by the disulfide-bonded trimeric amino termini and dimeric carboxyl termini. (B) The dimerization of the CysD domains will interact maximally if each layer of MUC2 polymer rings is partly dislocated.