The functions of the A1A2A3 domains in von Willebrand factor include multimerin 1 binding

Summary

Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (K_D: 2.0 ± 0.4 nM), whereas the individual VWF A1 (K_D: 39.3 ± 7.7 nM) and A3 domains (K_D: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbD binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates.

Keywords

von Willebrand factor - platelet glycoproteins - adhesion molecules - collagens

 

Conflicts of interest

None declared.

• References

• 1 Springer TA. von Willebrand factor, Jedi knight of the bloodstream. Blood 2014; 124: 1412-1425.
• 2 Savage B, Sixma JJ, Ruggeri ZM. Functional self-association of von Willebrand factor during platelet adhesion under flow. Proc Natl Acad Sci USA 2002; 99: 425-430.
• 3 De Ceunynck K, De Meyer SF, Vanhoorelbeke K. Unwinding the von Willebrand factor strings puzzle. Blood 2013; 121: 270-277.
• 4 Colace TV, Diamond SL. Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow. Arterioscler Thromb Vasc Biol 2013; 33: 105-113.
• 5 Dayananda KM, Singh I, Mondal N. et al. von Willebrand factor self-association on platelet GpIbalpha under hydrodynamic shear: effect on shear-induced platelet activation. Blood 2010; 116: 3990-3998.
• 6 Auton M, Sowa KE, Smith SM. et al. Destabilization of the A1 domain in von Willebrand factor dissociates the A1A2A3 tridomain and provokes spontaneous binding to glycoprotein Ibalpha and platelet activation under shear stress. J Biol Chem 2010; 285: 22831-22839.
• 7 Cruz MA, Diacovo TG, Emsley J. et al. Mapping the glycoprotein Ib-binding site in the von willebrand factor A1 domain. J Biol Chem 2000; 275: 19098-19105.
• 8 Emsley J, Cruz M, Handin R. et al. Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273: 10396-10401.
• 9 Peterson DM, Stathopoulos NA, Giorgio TD. et al. Shear-induced platelet aggregation requires von Willebrand factor and platelet membrane glycoproteins Ib and IIb-IIIa. Blood 1987; 69: 625-628.
• 10 Tasneem S, Adam F, Minullina I. et al. Platelet adhesion to multimerin 1 in vitro: influences of platelet membrane receptors, von Willebrand factor and shear. J Thromb Haemost 2009; 07: 685-692.
• 11 Hayward CP, Hassell JA, Denomme GA. et al. The cDNA sequence of human endothelial cell multimerin A unique protein with RGDS, coiled-coil, and epidermal growth factor-like domains and a carboxyl terminus similar to the globular domain of complement C1q and collagens type VIII and X. J Biol Chem 1995; 270: 18246-18251.
• 12 Hayward CP, Warkentin TE, Horsewood P. et al. Multimerin: a series of large disulfide-linked multimeric proteins within platelets. Blood 1991; 77: 2556-2560.
• 13 Jeimy SB, Tasneem S, Cramer EM. et al. Multimerin 1. Platelets 2008; 19: 83-95.
• 14 Tasneem S, Reheman A, Ni H. et al. Mice with deleted multimerin 1 and alphasynuclein genes have impaired platelet adhesion and impaired thrombus formation that is corrected by multimerin 1. Thromb Res 2010; 125: e177-e183.
• 15 Hayward CP, Bainton DF, Smith JW. et al. Multimerin is found in the alphagranules of resting platelets and is synthesized by a megakaryocytic cell line. J Clin Invest 1993; 91: 2630-2639.
• 16 Hayward CP, Cramer EM, Song Z. et al. Studies of multimerin in human endothelial cells. Blood 1998; 91: 1304-1317.
• 17 Yee A, Gildersleeve RD, Gu S. et al. A von Willebrand factor fragment containing the D’D3 domains is sufficient to stabilize coagulation factor VIII in mice. Blood 2014; 124: 445-452.
• 18 Hayward CP, Furmaniak-Kazmierczak E, Cieutat AM. et al. Factor V is complexed with multimerin in resting platelet lysates and colocalizes with multimerin in platelet alpha-granules. J Biol Chem 1995; 270: 19217-19224.
• 19 Jeimy SB, Woram RA, Fuller N. et al. Identification of the MMRN1 binding region within the C2 domain of human factor V. J Biol Chem 2004; 279: 51466-51471.
• 20 Jeimy SB, Fuller N, Tasneem S. et al. Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation. Thromb Haemost 2008; 100: 1058-1067.
• 21 Adam F, Zheng S, Joshi N. et al. Analyses of cellular multimerin 1 receptors: in vitro evidence of binding mediated by alphaIIbbeta3 and alphavbeta3. Thromb Haemost 2005; 94: 1004-1011.
• 22 Sixma JJ, Schiphorst ME, Verweij CL. et al. Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin. Eur J Biochem 1991; 196: 369-375.
• 23 Lankhof H, van Hoeij M, Schiphorst ME. et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75: 950-958.
• 24 Hoylaerts MF, Yamamoto H, Nuyts K. et al. von Willebrand factor binds to native collagen VI primarily via its A1 domain. Biochem J 1997; 324: 185-191.
• 25 Mazzucato M, Spessotto P, Masotti A. et al. Identification of domains responsible for von Willebrand factor type VI collagen interaction mediating platelet adhesion under high flow. J Biol Chem 1999; 274: 3033-3041.
• 26 Flood VH, Gill JC, Christopherson PA. et al. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost 2012; 10: 1417-1424.
• 27 Flood VH, Schlauderaff AC, Haberichter SL. et al. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 2015; 125: 2297-2304.
• 28 Lankhof H, Damas C, Schiphorst ME. et al. von Willebrand factor without the A2 domain is resistant to proteolysis. Thromb Haemost 1997; 77: 1008-1013.
• 29 Miyata S, Goto S, Federici AB. et al. Conformational changes in the A1 domain of von Willebrand factor modulating the interaction with platelet glycoprotein Ibalpha. J Biol Chem 1996; 271: 9046-9053.
• 30 Miyata S, Ruggeri ZM. Distinct structural attributes regulating von Willebrand factor A1 domain interaction with platelet glycoprotein Ibalpha under flow. J Biol Chem 1999; 274: 6586-6593.
• 31 Dong JF, Berndt MC, Schade A. et al. Ristocetin-dependent, but not botrocetindependent, binding of von Willebrand factor to the platelet glycoprotein Ib-IX-V complex correlates with shear-dependent interactions. Blood 2001; 97: 162-168.
• 32 Luken BM, Winn LY, Emsley J. et al. The importance of vicinal cysteines, C1669 and C1670, for von Willebrand factor A2 domain function. Blood 2010; 115: 4910-4913.
• 33 Zhang Q, Zhou YF, Zhang CZ. et al. Structural specializations of A2, a forcesensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci USA 2009; 106: 9226-9231.
• 34 Auton M, Sowa KE, Behymer M. et al. N-terminal flanking region of A1 domain in von Willebrand factor stabilizes structure of A1A2A3 complex and modulates platelet activation under shear stress. J Biol Chem 2012; 287: 14579-14585.
• 35 Fu X, Chen J, Gallagher R. et al. Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region. Blood 2011; 118: 5283-5291.
• 36 Da Q, Behymer M, Correa JI. et al. Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress. Blood 2014; 123: 2715-2721.
• 37 Scaglione GL, Lancellotti S, Papi M. et al. The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. J Thromb Haemost 2013; 11: 1688-1698.
• 38 Nishio K, Anderson PJ, Zheng XL. et al. Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc Natl Acad Sci USA 2004; 101: 10578-10583.
• 39 Huizinga EG, Martijn vdPR, Kroon J. et al. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 05: 1147-1156.
• 40 Lenting PJ, Westein E, Terraube V. et al. An experimental model to study the in vivo survival of von Willebrand factor Basic aspects and application to the R1205H mutation. J Biol Chem 2004; 279: 12102-12109.
• 41 Zhang X, Halvorsen K, Zhang CZ. et al. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 324: 1330-1334.
• 42 Hulstein JJ, Lenting PJ, de Laat B. et al. beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Blood 2007; 110: 1483-1491.
• 43 Lisman T, Raynal N, Groeneveld D. et al. A single high-affinity binding site for von Willebrand factor in collagen III, identified using synthetic triple-helical peptides. Blood 2006; 108: 3753-3756.
• 44 Zhang P, Pan W, Rux AH. et al. The cooperative activity between the carboxylterminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow. Blood 2007; 110: 1887-1894.
• 45 Hayward CP, Smith JW, Horsewood P. et al. p-155, a multimeric platelet protein that is expressed on activated platelets. J Biol Chem 1991; 266: 7114-7120.
• 46 Beumer S, Heijnen HF, IJsseldijk MJ. et al. Platelet adhesion to fibronectin in flow: the importance of von Willebrand factor and glycoprotein Ib. Blood 1995; 86: 3452-3460.
• 47 Inoue O, Suzuki-Inoue K, Ozaki Y. Redundant mechanism of platelet adhesion to laminin and collagen under flow: involvement of von Willebrand factor and glycoprotein Ib-IX-V. J Biol Chem 2008; 283: 16279-16282.
• 48 Flood VH, Gill JC, Christopherson PA. et al. Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease. J Thromb Haemost 2012; 10: 1425-1432.
• 49 Shankaran H, Alexandridis P, Neelamegham S. Aspects of hydrodynamic shear regulating shear-induced platelet activation and self-association of von Willebrand factor in suspension. Blood 2003; 101: 2637-2645.
• 50 Martin C, Morales LD, Cruz MA. Purified A2 domain of von Willebrand factor binds to the active conformation of von Willebrand factor and blocks the interaction with platelet glycoprotein Ibalpha. J Thromb Haemost 2007; 05: 1363-1370.