Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2

ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this review, we a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b) address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c) indicate the direction of future investigations

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Structure and function of von Willebrand factor: The role of C-terminal cystine knot and von Willebrand factor C domains

Japanese Journal of Thrombosis and Hemostasis ◽

10.2491/jjsth.28.64 ◽

2017 ◽

Vol 28 (1) ◽

pp. 64-69

Author(s):

Yongchol SHIN

Keyword(s):

Von Willebrand Factor ◽

Structure And Function ◽

Cystine Knot ◽

Factor C ◽

And Function ◽

Von Willebrand ◽

Willebrand Factor

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A single von Willebrand factor C-domain protein acts as an extracellular pattern-recognition receptor in the river prawn Macrobrachium nipponense

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013270 ◽

2020 ◽

Vol 295 (30) ◽

pp. 10468-10477

Author(s):

Nan Qin ◽

Hehe Sun ◽

Meike Lu ◽

Jianhui Wang ◽

Ting Tang ◽

...

Keyword(s):

Pattern Recognition ◽

Von Willebrand Factor ◽

Pattern Recognition Receptor ◽

Diaminopimelic Acid ◽

Macrobrachium Nipponense ◽

Imd Pathway ◽

Factor C ◽

Von Willebrand ◽

Willebrand Factor ◽

Recognition Receptor

The single von Willebrand factor C-domain proteins (SVWCs) are mainly found in arthropods. Their expression may be regulated by several environmental stresses, including nutritional status and bacterial and viral infections. However, the underlying regulatory mechanism is unclear. In the present study, we identified a member of the SVWC family from the river prawn Macrobrachium nipponense as a soluble and bacteria-inducible pattern-recognition receptor (designated MnSVWC). In vitro, recombinant MnSVWC exhibited pronounced binding and Ca2+-dependent agglutinating abilities against diverse microbes, including Gram-negative bacteria (i.e. Escherichia coli and Aeromonas victoria), Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), and yeast (Pichia pastoris). ELISA assays revealed that recombinant MnSVWC recognizes a broad range of various pathogen-associated molecular patterns (PAMPs) and has high affinity to lipopolysaccharide and lysine-type and diaminopimelic acid–type peptidylglycan and d-galactose and low affinity to d-mannan and β-1,3-glucan. Mutant MnSVWCP57A with an impaired Glu-Pro-Asn (EPN) motif displayed reduced affinity to all these PAMPs to varying extent. Moreover, MnSVWC bound to the surface of hemocytes and promoted their phagocytic activity and clearance of invasive bacteria. RNAi-mediated MnSVWC knockdown in prawn reduced the ability to clear invading bacteria, but did not block the activities of the Toll pathway or the arthropod immune deficiency (IMD) pathway, or the expression of antimicrobial peptide genes. These results indicate that MnSVWC functions as an extracellular pattern-recognition receptor in M. nipponense that mediates cellular immune responses by recognizing PAMPs, agglutinating invasive microbes, and promoting phagocytosis in hemocytes.

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