TO THE EDITOR:

von Willebrand factor (VWF) monomers dimerize through their C-terminal domain in the endoplasmic reticulum (ER). The unusual process of disulfide bond formation between N-terminal D′D3 assemblies (Figure 1) of neighboring dimers during tubule formation in the Golgi apparatus then forms the ultralong, tail-to-tail, head-to-head concatemers required for VWF activation in hemostasis.1-5  C-terminally truncated VWF fragments are secreted as mixtures of monomers and dimers; the monomers contain 2 free cysteines, Cys-1099 and Cys-1142, which were proposed to form the dimerizing interchain disulfide bonds. However, chemical determination of disulfide bonds in VWF is challenging7-9  and only the Cys-1142/Cys-1142′ disulfide has been confirmed. Surprisingly, a recent VWF D′D3 monomer crystal structure showed burial of Cys-1099 and Cys-1142, thus revealing how these residues are protected from disulfide bond formation in the ER, but little about disulfide...

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