In the present study, we re-annotated von Willebrand factor (VWF), assigned its entire sequence to specific modules, and related these modules to structure using electron microscopy (

The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-Å crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the ␣4 helix, and a cis-proline. The central ␤4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the ␤4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal ␣6-helix. The ␣6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure. Although there is great interest in the use of mechanical force to unfold protein domains and gain insights into the structural factors that govern mechanical stability, there are, as yet, few structural studies on domains that have evolved to unfold in the course of normal physiology and serve as biological force sensors (1). Von Willebrand factor (VWF) senses the high vascular flow rates (shear) found at sites of arterial bleeding and cross-links platelets to plug vessels in hemostasis. High shear activates binding of the A1 domain in VWF to platelet GPIb, and facilitates binding of VWF through its A3 domain to subendothelial collagen exposed at sites of vessel injury. The force-sensing A2 domain is located in between the A1 and A3 domains (2, 3).Hemostatic potential greatly increases with VWF length, which is tightly regulated in vivo (2, 3). The 240,000-Mr VWF monomer is dimerized through disulfide bonds at its C terminus (COC) and then concatenated through specific disulfide bonds at its N terminus (NON) into multimers up to Ϸ50 ϫ 10 6 Mr (Fig. 1A). VWF is stored in granules in endothelial cells in an ultralarge form (ULVWF) that is secreted in response to thrombogenic stimuli. Within 2 hours after release into the circulation, ULVWF is converted by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) to smaller multimers with a wide range of lengths that are characteristic of the circulating pool of VWF (4). Cleavage depends on hydrodynamic shear force, and occurs within the A2 domain at its Tyr 1605 -Met 1606 bond. Genetic or acquired deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura, a life-threatening disease in which microvascular thrombi form in arterioles and capillaries. Conversely, mutations in the A2 domain cause a bleeding disorder, type 2A von Willebrand disease (VWD), in which VWF multimers are smaller in size than in healthy individuals and have less hemostatic potential (2, 5, 6).Models of the A2 domain suggest that the ADAMTS...

Purpose -The purpose of this paper is to investigate if consumer buying motives regarding organic food in emerging economies China and Brazil are culture bound or determined by key characteristics of the product. Design/methodology/approach -A survey was collected in Guangzhou, China, and Porto Alegre, Brazil. Data were analyzed by means of structural equation modeling, checking for measurement invariance between samples. Findings -The reasons why Brazilian and Chinese consumers buy organic food are strikingly similar to what is found in Europe and North America. Consumers' attitude toward buying organic food is strongly linked to beliefs about its healthiness, taste and environmental friendliness. Also, consumer attitudes toward buying organic food are positively related to what Schwartz's "Universalism" values in all studied cultures. Research limitations/implications -Correlational (survey) data do not allow conclusions about causality and conclusions are limited by the covered countries and products. Practical implications -Key consumer value propositions with respect to organic food seem crossculturally valid and universally accepted by a segment of customers that share these values. Hence, organic food can be marketed globally based on a universal set of key value propositions. The same could be true for other global products sharing similar types of certifiable value propositions.

At the acidic pH of the trans-Golgi and Weibel-Palade bodies (WPBs), but not at the alkaline pH of secretion, the C-terminal ∼1350 residues of von Willebrand factor (VWF) zip up into an elongated, dimeric bouquet. Six small domains visualized here for the first time between the D4 and cystine-knot domains form a stem. The A2, A3, and D4 domains form a raceme with three pairs of opposed, large, flower-like domains. N-terminal VWF domains mediate helical tubule formation in WPBs and template N-terminal disulphide linkage between VWF dimers, to form ultralong VWF concatamers. The dimensions we measure in VWF at pH 6.2 and 7.4, and the distance between tubules in nascent WPB, suggest that dimeric bouquets are essential for correct VWF dimer incorporation into growing tubules and to prevent crosslinking between neighbouring tubules. Further insights into the structure of the domains and flexible segments in VWF provide an overall view of VWF structure important for understanding both the biogenesis of ultralong concatamers at acidic pH and flow-regulated changes in concatamer conformation in plasma at alkaline pH that trigger hemostasis.