Overview of relevant cysteine residues in VWF. The VWF protein sequence contains 234 cysteine residues, representing 8.3% of the total amino acid composition, a number that is fourfold higher than the average in human proteins. Cysteines contribute to the folding of the domains that characterize the VWF structure. Some of these cysteines form disulfide bridges during synthesis, but are susceptible to reduction following secretion. Consequently, they are converted into free thiols (positions 889, 898, 2448, 2451, 2453, 2490, 2491, 2528, and 2533).7,10 Other cysteines engage in intersubunit disulfide bonding (positions 2771, 2773, and 2811 in the CK domain and positions 1142, 1222, 1225, and 1227 in the D3 domain).1,11,12 N-terminal multimerization involves disulfide isomerase activity located in the D1 and D2 domains (motif 159-162 and 521-524).13 Given their importance for the VWF structure, it is not surprising that mutations of cysteines may affect different stages of the VWF life cycle. Examples hereof (red boxes) include mutations affecting multimerization, storage in WPBs, secretion, and clearance.14-18
