von Willebrand factor assembly and secretion.

During its life history, von Willebrand factor (VWF) experiences a remarkable sequence of conformational changes that are triggered by differences in pH between the endoplasmic reticulum (ER), Golgi and extracellular environments. VWF subunits dimerize in the ER and assemble into disulfide-linked multimers in the trans-Golgi, which lacks known chaperones and has an acidic pH that inhibits disulfide rearrangement. VWF has circumvented these problems by evolving N-terminal domains that function as an oxidoreductase at the low pH of the Golgi. VWF multimers also condense into tightly packed, tubular arrays for storage in the Weibel-Palade bodies of endothelial cells. Like multimer assembly, tubular packing depends on low pH and Ca2+. Upon secretion, exposure to the neutral pH of the extracellular environment allows enormous VWF multimers to uncoil without tangling, which is crucial for hemostasis. Recent studies have identified some of the biochemical and structural properties that underlie these self-organizing behaviors.