Fig. 5.

Model for the assembly, tubular packing, and secretion of VWF multimers. (A and B) In the ER, proVWF subunits dimerize through disulfide bonds between C-terminal CK domains (small gray spheres). The propeptide consists of domains D1 (“1,” yellow) and D2 (“2,” orange) and is linked to D′D3 of the mature subunit (“3,” blue) by a furin cleavage site (green). Two potential orientations of the propeptide are distinguished by whether homodimer contacts involve domain D1 (A) or D2 (B). In either case, pH-dependent interactions bring two D′D3 domains together and facilitate intersubunit disulfide bond formation. (C) The propeptide (yellow) and dimeric D′D3 domains (blue) pack into a helix surrounded by the C-terminal remainder of the VWF subunits (gray). (D) Secretion exposes the tubules to blood at pH 7.4, which destabilizes the contacts between propeptide and D′D3 domains and allows extension of the multimer.