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Thromb Haemost 1993; 70(06): 1058-1062
DOI: 10.1055/s-0038-1649725
Original Article
Von Willebrand Factor and Endothelial Cells
Schattauer GmbH Stuttgart

Effect of Type IIB von Willebrand Disease Mutation Arg(545)Cys on Platelet Glycoprotein Ib Binding – Studies with Recombinant von Willebrand Factor

Aida Inbal
1   Thrombosis and Hemostasis Center, Hematology Institute Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel
,
Nurit Kornbrot
1   Thrombosis and Hemostasis Center, Hematology Institute Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel
,
Paul Harrison
2   Coagulation Research Unit, The Rayne Institute, St. Thomas' Hospital, London, UK
,
Anna M Randi
4   Department of Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
,
J Evan Sadler
3   Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO, USA
4   Department of Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
› Author Affiliations
Further Information

Publication History

Received 21 June 1993

Accepted after revision 19 August 1993

Publication Date:
06 July 2018 (online)

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Summary

Type IIB von Willebrand disease (vWD) is characterized by a selective loss of high molecular weight von Willebrand factor (vWF) multimers in plasma due to their abnormally enhanced reactivity with platelets. Several missense mutations in the platelet glycoprotein lb (GPIb) binding domain of vWF were recently characterized that cause type IIB vWD. The effect of type IIB mutation Arg(545)Cys on vWF binding to platelet GPIb was studied using recombinant wild type (rvWFWT) and mutant rvWFR545C expressed in COS-7 cells. In the absence of ristocetin, 50% of rvWFR545C bound spontaneously to platelet GPIb and the binding increased to 70% in the presence of 0.2 mg/ml ristocetin; rvWFWT did not bind significantly under either condition. Botrocetin-induced binding of rvWFR545C was only slightly increased compared to rvWFWT. These data demonstrate that the Arg(545)Cys mutation increases the affinity of vWF for GPIb, resulting in the characteristic gain-of-function type IIB vWD phenotype.

 

  • References

  • 1 Girma JP, Meyer D, Verweij CL, Pannekoek H, Sixma JJ. Structure-function relationship of human von Willebrand factor. Blood 1987; 70: 605-611
    PubMedSearch in Google Scholar
  • 2 Ruggeri ZM, Ware J. The structure and function of von Willebrand factor. Thromb Haemostas 1992; 67: 594-599
    PubMedSearch in Google Scholar
  • 3 Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273
    CrossrefPubMedSearch in Google Scholar
  • 4 Sadler JE. Von Willebrand factor. J Biol Chem 1991; 266: 22777-22780
    PubMedSearch in Google Scholar
  • 5 Bockenstedt P, McDonagh J, Handin RI. The binding and covalent crosslinking of purified von Willebrand’s factor to native monometric collagen. J Clin Invest 1986; 78: 551-556
    CrossrefPubMedSearch in Google Scholar
  • 6 Roth GJ, Titani K, Hoyer LW, Hickey MJ. Localization of binding sites within human von Willebrand factor for monomeric Type III collagen. Biochemistry 1986; 25: 8357-8361
    CrossrefPubMedSearch in Google Scholar
  • 7 de GrootPG, Ottenhof-Povers M, van MourikJA, Sixma JJ. Evidence that the primary binding site of von Willebrand factor that mediated platelet adhesion on subendothelium is not collagen. J Clin Invest 1988; 82: 65-73
    CrossrefPubMedSearch in Google Scholar
  • 8 Ruggeri ZM, De MarcoL, Gatti L, Bader R, Montgomery RR. Platelets have more than one binding site for von Willebrand factor. J Clin Invest 1988; 82: 65-73
    CrossrefPubMedSearch in Google Scholar
  • 9 Fujimura Y, Titani K, Holland LZ, Russell SR, Roberts JR, Elder JH, Ruggeri ZM, Zimmerman TS. Von Willebrand factor: A reduced and alkylated 52/48-KDa fragment beginning at amino-acid residue 449 contains the domain interacting with platelet glycoprotein Ib. J Biol Chem 1986; 261: 381-385
    PubMedSearch in Google Scholar
  • 10 Mohri H, Yoshioka A, Zimmerman TS, Ruggeri ZM. Isolation of von Willebrand factor domain interacting with platelet glycoprotein Ib heparin, and collagen and characterization of its three distinct functional sites. J Biol Chem 1989; 264: 17361-17367
    PubMedSearch in Google Scholar
  • 11 Andrews RK, Gorman JJ, Booth WJ, Corino GL, Castaldi PA, Berndt MC. Cross-linking of a monomeric 39/34-kDa dispase fragment of von Willebrand factor (Leu-480/Val-481-Gly-718) to the N-terminal region of the α-chain of membrane glycoprotein Ib on intact platelets with bis(sulfosuccinimidyl) suberate. Biochemistry 1989; 28: 8326-8336
    CrossrefPubMedSearch in Google Scholar
  • 12 Mohri H, Fujimura Y, Shima M, Yoshioka A, Houghten RA, Ruggeri ZM, Zimmerman TS. Structure of the von Willebrand factor domain interacting with glycoprotein Ib. J Biol Chem 1988; 263: 17901-17904
    PubMedSearch in Google Scholar
  • 13 Berndt MC, Ward CM, Booth WJ, Castaldi PA, Mazurov AV, Andrews RK. Identification of aspartic acid-514 through glutamic acid-542 as a glycoprotein-Ib-IX complex receptor recognition sequence in von Willebrand factor – mechanism of modulation of von Willebrand factor by ristocetin and botrocetin. Biochemistry 1992; 31: 11144-11151
    CrossrefPubMedSearch in Google Scholar
  • 14 Nachman RL, Jaffe EA, Weksler BB. Immunoinhibition of ristocetin-induced platelet aggregation. J Clin Invest 1977; 59: 143-148
    CrossrefPubMedSearch in Google Scholar
  • 15 Sugimoto M, Mohri H, McClintock RA, Ruggeri ZM. Identification of discontinuous von Willebrand factor sequences involved in complex formation with botrocetin: a model for the regulation of von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1991; 266: 18172-18178
    PubMedSearch in Google Scholar
  • 16 Ruggeri ZM, Pared FI, Mannucci PM, Ciavarella N, Zimmerman TS. Heightened interaction between platelets and factor VUI/von Willebrand factor in a new subtype of von Willebrand’s disease. N Engl J Med 1980; 302: 1047-1051
    CrossrefPubMedSearch in Google Scholar
  • 17 Ruggeri ZM, Lombardi R, Gatti L, Bader RC, Valsecchi C, Zimmerman TS. Type IIB von Willebrand’s disease: differential clearance of endogenous versus transfused large multimer von Willebrand factor. Blood 1982; 60: 1453-1456
    PubMedSearch in Google Scholar
  • 18 De MarcoL, Girolami A, Zimmerman TS, Ruggeri ZM. Interaction of purified type IIB von Willebrand factor with the platelet membrane glycoprotein Ib induces fibrinogen binding to the glycoprotein IIb/IIIa complex and initiates aggregation. Proc Natl Acad Sci USA 1985; 82: 7424-7428
    CrossrefPubMedSearch in Google Scholar
  • 19 De MarcoL, Mazzucato M, De RoiaD, Casonato A, Federici AB, Girolami A, Ruggeri ZM. Distinct abnormalities in the interaction of purified types IIA and IIB von Willebrand factor with the two platelet binding sites glycoprotein complexes Ib-IX and IIb-IIIa. J Clin Invest 1990; 86: 785-792
    CrossrefPubMedSearch in Google Scholar
  • 20 de GrootPG, Federici AB, de BoerHC, d’Alessio P, Mannucci PM, Sixma JJ. Von Willebrand factor synthesized by endothelial cells from a patient with type IIB von Willebrand disease supports platelet adhesion normally but has an increased affinity for platelets. Proc Natl Acad Sci USA 1989; 86: 3793-3797
    CrossrefPubMedSearch in Google Scholar
  • 21 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one diisulfide loop between proposed platelet glycoprotein lb binding sequences. J Clin Invest 1991; 87: 1220-1226
    CrossrefPubMedSearch in Google Scholar
  • 22 Cooney KA, Nichols WC, Bruck ME, Bahou WF, Shapiro AD, Bowie EJW, Gralnick HR, Ginsburg D. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GPIb binding domain. J Clin Invest 1991; 87: 1227-1233
    CrossrefPubMedSearch in Google Scholar
  • 23 Ware J, Dent JA, Azuma H, Sugimoto M, Kyrle PA, Yoshioka A, Ruggeri ZM. Identification of a point mutation in type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor. Proc Natl Acad Sci USA 1991; 88: 2946-2950
    CrossrefPubMedSearch in Google Scholar
  • 24 Ribba AS, Voorberg J, Meyer D, Pannekoek H, Pietu G. Characterization of recombinant von Willebrand factor corresponding to mutations in type IIA and type IIB von Willebrand disease. J Biol Chem 1992; 267: 23209-23215
    PubMedSearch in Google Scholar
  • 25 Lillicrap D, Murray EW, Benford K, Blanchette VS, Rivard GE, Wensley R, Giles AR. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain in patients with type IIB von Willebrand’s disease. Br J Haematol 1991; 79: 612-617
    CrossrefPubMedSearch in Google Scholar
  • 26 Murray EW, Giles AR, Lillicrap D. Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib binding domain of von Willebrand factor causing type IIB von Willebrand disease. Am J Hum Genet 1992; 50: 199-207
    PubMedSearch in Google Scholar
  • 27 Donner M, Kristofferson EC, Lenk H, Scheibel E, Dahlback B, Nilsson IM, Holmberg L. Type IIB von Willebrand’s disease: gene mutations and clinical presentation in nine families from Denmark Germany and Sweden. Br J Haematol 1992; 82: 58-65
    CrossrefPubMedSearch in Google Scholar
  • 28 Ginsburg D, Sadler JE. Von Willebrand disease: A database of point mutations insertions and deletions. Thromb Haemostas 1993; 69: 177-184
    PubMedSearch in Google Scholar
  • 29 Kroner PA, Kluessendorf ML, Scott JP, Montgomery RR. Expressed full length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets. Blood 1992; 79: 2048-2055
    PubMedSearch in Google Scholar
  • 30 Cooney KA, Lyons SE, Ginsburg D. Functional analysis of a type IIB von Willebrand disease missense mutation. Increased binding of large von Willebrand factor multimers to platelets. Proc Natl Acad Sci USA 1992; 89: 2869-2872
    CrossrefPubMedSearch in Google Scholar
  • 31 Randi AM, Jorieux S, Tuley EA, Mazurier C, Sadler JE. Recombinant von Willebrand factor Arg578Gln. A type lib von Willebrand disease mutation affects binding to glycoprotein lb but not to collagen or heparin. J Biol Chem 1992; 267: 21187-21192
    PubMedSearch in Google Scholar
  • 32 Donner M, Anderssen AM, Kristoffersson AC, Nilsson IM, Dahlback B, Holmberg L. An Arg545-Cys545 substitution mutation of the von Willebrand factor in type IIB von Willebrand’s disease. Eur J Haematol 1991; 47: 342-345
    PubMedSearch in Google Scholar
  • 33 Wagner DD, Saffaripour S, Bonfanti R, Sadler JE, Cramer EM, Chapman B, Mayadas TN. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell 1991; 64: 403-413
    CrossrefPubMedSearch in Google Scholar
  • 34 Tuley EA, Gaucher C, Jorieux S, Worrall NK, Sadler JE, Mazurier C. Expression of von Willebrand factor “Normandy”: An autosomal mutation that mimics hemophilia A. Proc Natl Acad Sci USA 1991; 88: 6377-6381
    CrossrefPubMedSearch in Google Scholar
  • 35 Raines G, Aumann G, Skyes S, Street A. Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel. Thromb Res 1990; 60: 201-212
    CrossrefPubMedSearch in Google Scholar
  • 36 Mazurier C, Gaucher C, Jorieux S, Parquet-Gernez A, Goudemand M. Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling. Br J Haematol 1990; 76: 372-379
    CrossrefPubMedSearch in Google Scholar
  • 37 Krohn K, Sherman L, Welch M. Studies of radioiodinated fibrinogen. Biochim Biophys Acta 1972; 285: 404-413
    CrossrefPubMedSearch in Google Scholar
  • 38 Soutar AK, Wade DP. In: Protein Function. Creighton TE. editor Press Oxford University Press Oxford; UK: 1990. pp 69-71
  • 39 Aly AM, Arai M, Hoyer LW. Cysteamine enhances the procoagulant activity of factor VIII – East Hartford a dysfunctional protein due to a light chain thrombin cleavage site mutation (Arginine-1689 to cysteine). J Clin Invest 1992; 89: 1375-1381
    CrossrefPubMedSearch in Google Scholar
  • 40 Howard MA, Perkin J, Salem HH, Firkin BG. The agglutination of human platelets by botrocetin: evidence that botrocetin and ristocetin act at different sites on the factor VIII molecule and platelet membrane. Br J Hematol 1984; 57: 25-35
    CrossrefPubMedSearch in Google Scholar
  • 41 Girma JP, Takahashi Y, Yoshioka A, Diaz J, Meyer D. Ristocetin and botrocetin involve two distinct domains of von Willebrand factor for binding to platelet membrane glycoprotein Ib. Thromb Haemost 1990; 64: 326-332
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR. The effect of AB0 blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695
    CrossrefPubMedSearch in Google Scholar