pH-dependent homotypic association involves specific pairing between the A2, A3, D4 and six smaller domains between D4 and CK ( Fig. 1C). ![]() ![]() The term dimeric bouquet describes the appearance in EM of the A2, A3, and D4 domains as six flowers in a raceme, and C-terminal domains as a stem. N-linked glycans are processed, and O-linked glycans are added.Ī previously undescribed dimeric bouquet forms at pH 6.2 in the C-terminal portion of VWF (Y.-F. ProVWF dimers are then transported from the ER (pH approximately 7.4) to the Golgi (pH approximately 6.2). N-linked glycans are added in the ER, most disulphide bonds are formed, and proVWF is dimerised through formation of inter-monomer disulphide bonds in the C-terminal cystine-knot (CK) domain ( Fig. 1B). VWF glycoprotein is biosynthesised as a preproprotein the signal sequence is removed during translocation into the endoplasmic reticulum (ER) ( Fig. 1A). Multiple biological specialisations are required for the biosynthesis of the largest known soluble vertebrate protein. EM evidence for N-terminal D1-D2 homodimerisation and the helical assembly is from. EM evidence for C-terminal pH-regulated dimeric bouquet and domain shapes is from Y.-F. (B–E) Scheme for biosynthesis, helical assembly, and secretion. N and O-linked glycans are closed and open lollipops, respectively. Cysteines are vertical lines and are connected for chemically determined disulphide bonds. (A) Primary structure and domain organisation of VWF. Mutations in von Willebrand disease (VWD) both contribute to and are illuminated by understanding of VWF biology.īiosynthesis, helical assembly, and secretion of VWF concatamers. I review recent advances in our understanding of the biosynthesis, activation by elongational flow, mechanoenzymatic length regulation, and biophysics of the A1 and A2 domains of VWF. These forces activate both the haemostatic function and thrombotic pathology of VWF. The enormous length of VWF concatamers brings them into a range where the hydrodynamic forces acting on them in the circulation are highly significant, like on blood cells in the circulation, whereas such forces on other plasma proteins and cell surface receptors are negligible. ‘Multimer’ denotes both branched and unbranched polymers because the biology and physics of VWF are intertwined with the linear nature of its polymer, I prefer the more specific term ‘concatamer’ for a linear polymer. ![]() VWF multimers are organised as long linear concatamers, in which each monomer disulphide bonds tail-to-tail at its C-terminus, and head-to-head at its N-terminus, with adjacent monomers ( Fig. 1). Different domains within VWF bind clotting factor VIII, collagen, platelet glycoprotein Ib (GPIb), and integrins α IIbβ 3 and α Vβ 3 ( Fig. 1A). Von Willebrand factor (VWF) is central in haemostasis and thrombosis in the rapid flow of the arteriolar circulation. Single molecule studies on the A1-GPIb receptor-ligand bond demonstrate a specialised flex-bond that enhances resistance to the strong hydrodynamic forces experienced at sites of haemorrhage. Recent structures of A2 and single molecule measurements of A2 unfolding and cleavage by ADAMTS13 illuminate the mechanisms of VWF length regulation. Elongational forces regulate haemostasis by activating binding of the A1 domain to platelet GPIbα, and over longer time periods, regulate VWF length by unfolding of the A2 domain for cleavage by ADAMTS13. Moreover, elongational hydrodynamic forces on VWF are strongest just where needed, when bound to the vessel wall, or in elongational flow in the circulation at sites of vessel rupture or vasoconstriction in haemostasis. VWF is longest at its site of secretion, where its haemostatic function is most important. Length regulation occurs post-secretion, by hydrodynamic force-regulated unfolding of the VWF A2 domain, and its cleavage by the plasma protease ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). Orderly assembly and storage of ultra-long concatamers in helical tubules, without crosslinking of neighboring tubules, enables unfurling during secretion without entanglement. Specialisations include a pH-regulated dimeric bouquet formed by the C-terminal half of VWF and helical assembly guided by the N-terminal half that templates inter-dimer disulphide bridges. ![]() Structural specialisations enable von Willebrand factor (VWF) to assemble during biosynthesis into helical tubules in Weibel-Palade bodies (WPB).
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