Von Willebrand factor folds into a bouquet.

The large glycoprotein von Willebrand factor (vWF) serves an important role in orchestrating the blood vessel’s response to injury. It is released from activated endothelial cells and forms long multimeric strings that bind exposed extracellular matrix and circulating platelets and thereby initiate the formation of a platelet plug sealing the wound. Central to this process is the rapid transition of multimeric vWF from a tightly packed storage form present in acidic intraendothelial granules, to the elongated string that is active at neutral vascular pH. In this issue of The EMBO Journal, Zhou and coworkers now provide compelling structural evidence for internal conformational changes that accompany this transition and thereby serve important regulatory functions. They show that the C-terminal part of the protein zips up into a dimeric bouquet at the acidic internal pH of the storage granules but opens up at the neutral pH of plasma, thereby assisting the establishment of elongated vWF strings capable of efficiently capturing platelets. Blood vessel wounds have to be repaired rapidly and in a tightly controlled manner to prevent excessive leakage and maintain vascular function. An immediate response to vessel injury is the formation of a platelet plug that is initiated by the acute release of vWF from activated endothelial cells. vWF is a multimeric glycoprotein that binds to platelet glycoprotein Ib and also other receptors on activated platelets. To efficiently capture platelets at sites of vessel injury vWF has a unique property, it forms elongated strings of covalently linked concatamers that can consist of 4100 vWF molecules and can span a length of more than 100 mm (making it the largest soluble protein in vertebrates). Importantly, string formation of vWF is tightly regulated and only occurs once the protein is released into the vasculature. Inside endothelial cells vWF multimers are stored as a condensed tubular form in acidic organelles, the WeibelPalade bodies (WPB; Sadler, 1998, 2009; Wagner, 1990; Metcalf et al, 2008; Valentijn et al, 2011). How is the switch from condensed tubules to elongated strings brought about and how is the tight packing of vWF concatamers in the WPB achieved? To answer these questions, we have to consider the complex structure and maturation of vWF. It is synthesized as a preproprotein at the ER with the signal peptide cleaved off following synthesis. In the ER, vWF dimerizes via interchain disulphide bond formation in the C-terminal cysteine-knot (CK) region (Figure 1A). Further maturation occurring in the Golgi apparatus includes furin cleavage between domains D2 and D0 and another interchain disulphide linkage between C3 domains of adjacent dimers. Thereby vWF forms long concatamers linked by tail–tail (C-terminal) and head–head (Nterminal) disulphides. To allow efficient and space-saving package into WPB, the vWF multimers are condensed by the formation of helical tubules, in which the D0D3 domains of neighbouring dimers are non-covalently joined via a dimer of the D1D2 propeptide that remains associated with the rest