Reactome | factor VIII + von Willebrand factor multimer -> factor VIII:von Willibrand factor multimer

factor VIII + von Willebrand factor multimer -> factor VIII:von Willibrand factor multimer

Stable Identifier

R-HSA-158118

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region

ReviewStatus

5/5

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factor VIII + von Willebrand factor multimer -> factor VIII:von Willibrand factor multimer

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Factor VIII (FVIII) binds to von Willebrand factor (vWF) to form a complex (Lollal P et al. 1988; Leyte A et al. 1989; Vlot et al. 1995). Antibody inhibition data, site-directed deletion and mutagenesis studies suggest that the acidic subdomain a3, C1 & C2 domains of the FVIII light chain together control high affinity binding to vWF (Foster PA et al. 1988; Leyte A et al. 1989, 1991; Shima M et al. 1993; Saenko EL et al. 1994; Saenko EL & Scandella D 1997; Jacquemin M et al. 2000). Structural studies using negative stain electron microscopy (EM) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) have revealed that the TIL’ domain of vWF interacts with the C1 domain of FVIII, the E’ domain of vWF bridges the TIL’ and D3 domains of vWF, whereas the D3 domain of vWF interacts with the C1 and C2 domains of FVIII (Yee A et al. 2015; Chiu PL et al. 2015). In addition, HDX-MS experiments showed that the FVIII a3 subdomain residues V1689-D1697 are directly involved in the interaction (Chiu PL et al. 2015). A combination of NMR spectroscopy and isothermal titration calorimetry (ITC) confirmed direct interaction between the a3 region of FVIII and the TIL’ domain of VWF mapping it to the residues in the two β-sheet regions on the VWF TIL’ domain (Dagil L et al. 2019). Further, tyrosine sulfation at residue 1699 is required for the interaction of FVIII with vWF (Leyte A et al. 1991). In the absence of sulfation at Y1699 in FVIII, the affinity for vWF was reduced by 5-fold (Leyte A et al. 1991). The nuclear magnetic resonance (NMR) spectrum studies of the complex between FVIII and vWF showed significantly larger residue-specific chemical shift changes when Y1699 was sulfated further highlighting the importance of FVIII sulfation at Y1699 for the binding affinity to vWF (Dagil L et al. 2019). The significance of the sulfation of FVIII at Y1699 in vivo is made evident by the presence of a Y1699F mutation that causes a moderate hemophilia A, likely due to reduced interaction with vWF and decreased plasma half-life (van den Biggelaar M et al. 2011). The vWF stabilizes FVIII, which otherwise has a very short half-life in the blood stream (Kaufman RJ et al. 1988). The interaction of FVIII with vWF allows thrombin to activate the bound FVIII and impedes cleavage of the molecules of nonactivated FVIII by the proteases FXa and activated protein C (APC) (Hamer RJ et al. 1987; Hill-Eubanks DC & Lollar P 1990; Koedam JA et al. 1990; Nogami K et al. 2002). Furthermore, vWF prevents the nonspecific binding of FVIII to the membranes of activated human platelets (Nesheim M et al. 1991; Li X & Gabriel DA 1997).

Factor VIII is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide (Vehar et al. 1984). Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).

In vitro, vWF facilitates the association of FVIII chains and the retention of procoagulant activity in the conditioned medium of cells producing FVIII (Kaufman RJ et al. 1988; Wise RJ et al. 1991). Similar data have been obtained for re-association of FVIII chains in solution (Fay PJ 1988). In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex.

Literature References

PubMed ID	Title	Journal	Year
7756647	The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor Vlot, AJ, Koppelman, SJ, van den Berg, MH, Bouma, BN, Sixma, JJ	Blood	1995
26065653	Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII Yee, A, Oleskie, AN, Dosey, AM, Kretz, CA, Gildersleeve, RD, Dutta, S, Su, M, Ginsburg, D, Skiniotis, G	Blood	2015
3524673	Amino acid sequence of human von Willebrand factor Titani, K, Kumar, S, Takio, K, Ericsson, LH, Wade, RD, Ashida, K, Walsh, KA, Chopek, MW, Sadler, JE, Fujikawa, K	Biochemistry	1986
2505252	Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin Hill-Eubanks, DC, Parker, CG, Lollar, P	Proc Natl Acad Sci U S A	1989
6438527	Structure of human factor VIII Vehar, GA, Keyt, B, Eaton, D, Rodriguez, H, O'Brien, DP, Rotblat, F, Oppermann, H, Keck, R, Wood, WI, Harkins, RN, Tuddenham, EG, Lawn, RM, Capon, DJ	Nature	1984
3082357	Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity. Eaton, D, Rodriguez, H, Vehar, GA	Biochemistry	1986
26065652	Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry Chiu, PL, Bou-Assaf, GM, Chhabra, ES, Chambers, MG, Peters, RT, Kulman, JD, Walz, T	Blood	2015
3134349	Association of the factor VIII light chain with von Willebrand factor Lollar, P, Hill-Eubanks, DC, Parker, CG	J Biol Chem	1988
31349985	Interaction Between the a3 Region of Factor VIII and the TIL'E' Domains of the von Willebrand Factor Dagil, L, Troelsen, KS, Bolt, G, Thim, L, Wu, B, Zhao, X, Tuddenham, EGD, Nielsen, TE, Tanner, DA, Faber, JH, Breinholt, J, Rasmussen, JE, Hansen, DF	Biophys. J.	2019