A Binding Site for Heparin in the Apple 3 Domain of Factor XI

Ho, David; Badellino, Karen O.; Baglia, Frank A.; Walsh, Peter N.

doi:10.1074/jbc.273.26.16382

Cited by 82 publications

(99 citation statements)

References 42 publications

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“…Due to its binding to the forming thrombus in vivo, cell-free RNA may become concentrated at these sites and serves as cofactor for protease activation. Cellular binding sites for factors XII and XI (32,33) could be shared by RNA, and heparin may compete for factor XII/XI binding to RNA, thereby providing an alternate mechanism of anticoagulation.…”

Section: Discussionmentioning

confidence: 99%

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation

Kannemeier

Shibamiya²,

Nakazawa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

492

463

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Upon vascular injury, locally controlled haemostasis prevents lifethreatening blood loss and ensures wound healing. Intracellular material derived from damaged cells at these sites will become exposed to blood components and could contribute to blood coagulation and pathological thrombus formation. So far, the functional and mechanistic consequences of this concept are not understood. Here, we present in vivo and in vitro evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation. Extracellular RNA was found to augment (auto-)activation of proteases of the contact phase pathway of blood coagulation such as factors XII and XI, both exhibiting strong RNA binding. Moreover, administration of exogenous RNA provoked a significant procoagulant response in rabbits. In mice that underwent an arterial thrombosis model, extracellular RNA was found associated with fibrin-rich thrombi, and pretreatment with RNase (but not DNase) significantly delayed occlusive thrombus formation. Thus, extracellular RNA derived from damaged or necrotic cells particularly under pathological conditions or severe tissue damage represents the long sought natural ''foreign surface'' and provides a procoagulant cofactor template for the factors XII/XI-induced contact activation/amplification of blood coagulation. Extracellular RNA thereby reveals a yet unrecognized target for antithrombotic intervention, using RNase or related therapeutic strategies.contact phase activation ͉ thrombosis ͉ RNase ͉ vascular injury ͉ wound healing

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Section: Discussionmentioning

confidence: 99%

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation

Kannemeier

Shibamiya²,

Nakazawa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

492

463

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“…Thus, the defect in binding characterizing these mutants is exclusively due to their ability to interact with platelet membranes. As positive controls, we used the mutants K252A and K253A, which showed normal platelet binding but abnormal heparin binding (32); these mutants demonstrated normal HK and platelet binding. This further solidifies our contention that FXI platelet binding is specific and is mediated by specific amino acid residues Ser 248 , Arg 250 , Lys 255 , Leu 257 , and Gln 263 .…”

Section: The Effects Of Mutant Recombinant Factor XI Proteins In Coagmentioning

confidence: 99%

The Role of High Molecular Weight Kininogen and Prothrombin as Cofactors in the Binding of Factor XI A3 Domain to the Platelet Surface

Ho¹,

Badellino²,

Baglia³

et al. 2000

Journal of Biological Chemistry

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We have reported that prothrombin (1 M) is able to replace high molecular weight kininogen (45 nM) as a cofactor for the specific binding of factor XI to the platelet (Baglia, F. A., and Walsh, P. N. (1998) Biochemistry 37, 2271-2281). We have also determined that prothrombin fragment 2 binds to the Apple 1 domain of factor XI at or near the site where high molecular weight kininogen binds. A region of 31 amino acids derived from high molecular weight kininogen (HK31-mer) can also bind to factor XI (Tait, J. Coagulation factor XI (FXI)1 is a disulfide-linked homodimeric protein (160,000 Da) (1) that is cleaved by thrombin, FXIIa, or FXIa at a single peptide bond (Arg 369 -Ile 370 ) to give rise to FXIa (2-5). The primary structures of four repeat sequences (designated A1, A2, A3, and A4 or Apple domains) present in the heavy chain region of FXI have been elucidated from the sequence of cDNA inserts coding for FXI (1). Evidence exists for the presence of a FIX binding site on the A2 domain (6) and at the N terminus of the A3 domain (7,8), and a binding site for FXIIa in the A4 domain (9). In plasma, FXI circulates in a complex with high molecular weight kininogen (HK) (10, 11), an interaction that requires the A1 domain of FXI (12, 13) and the light chain of HK (14). FXI can also bind to prothrombin, which can displace HK bound to FXI and which binds to a site (Ala 45 -Ser 86 ) in the A1 domain that is within the HK-binding site (15). In the presence of HK or prothrombin, FXI can bind reversibly and specifically to high affinity sites on the surface of stimulated human platelets in the presence of zinc and calcium ions (15, 16). More specifically, this laboratory has demonstrated that the A3 domain of FXI is essential in the binding of FXI to platelets, since a recombinant A3 (rA3) domain of FXI demonstrated specific, saturable binding and effectively competed with radiolabeled FXI in binding to the platelet surface (17). The consequence of FXI binding to activated platelets is an acceleration of the rate of FXI activation by thrombin, FXIIa, or FXIa (15).Since both prothrombin (15, 18) and HK (14, 16, 19) have been shown to bind both to platelets (15,16,18,19) and to FXI (14, 15), one objective of the present study was to examine the mechanism by which HK and prothrombin promote the binding of FXI to the activated platelet, i.e. to determine whether either the FXI⅐HK complex or the FXI⅐prothrombin complex initially binds as an encounter complex to platelets via HK or prothrombin, or whether, alternatively either HK or prothrombin binds only to the FXI A1 domain resulting in exposure of the A3 domain platelet binding site. Another goal of the present study was to define the amino acids within the A3 domain of FXI that mediate its binding to platelets. The results of these studies, utilizing site-directed mutational analysis of recombinant FXI (rFXI) confirm and extend previous studies utilizing conformationally constrained synthetic peptides and the rA3 domain of FXI, which identified Arg 250 , Lys 255 , Phe 260...

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“…In addition FXI apple A1 binds to thrombin (42), an important endogenous activator of FXI in blood coagulation (43,44). FXI domain A3 has been shown to bind to platelets (45) and heparin (46), and domain A4 to FXIIa (47). Using a synthetic peptide approach Walsh and co-workers (48) demonstrated that FXI domain A2 binds FIX although this conclusion has been challenged by the recent study of Sun and Gailani (30) who used recombinant FX-PPK chimeras to show that the FIX-binding site is located in A3 rather than in A2.…”

Section: Fig 5 Transfer Of Ppk Apple Domain A2 Increases Hk Bindingmentioning

confidence: 99%

Mapping of the Discontinuous H-kininogen Binding Site of Plasma Prekallikrein

Renné¹,

Dedio²,

Meijers³

et al. 1999

Journal of Biological Chemistry

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Plasma prekallikrein, a zymogen of the contact phase system, circulates in plasma as heterodimeric complex with H-kininogen. The binding is mediated by the prekallikrein heavy chain consisting of four apple domains, A1 to A4, to which H-kininogen binds with high specificity and affinity (K D ‫؍‬ 1.2 ؋ 10 ؊8 M). Previous work had demonstrated that a discontinuous kininogen-binding site is formed by a proximal part located in A1, a distal part exposed by A4, and other yet unidentified portion(s) of the kallikrein heavy chain. To detect relevant binding segment(s) we recombinantly expressed single apple domains and found a rank order of binding affinity for kininogen of A2 > A4 Ϸ A1 > A3. Removal of single apple domains in prekallikrein deletion mutants reduced kininogen binding by 21 (A1), 64 (A2), and 24% (A4), respectively, whereas deletion of A3 was without effect. Transposition of homologous A2 domain from prekallikrein to factor XI conferred high-affinity kininogen binding from the former to the latter. The principal role of A2 for H-kininogen docking to the prekallikrein heavy chain was further substantiated by the finding that cleavage of a single peptide bond in A2 drastically diminished the H-kininogen binding affinity. Furthermore, the epitope of monoclonal antibody PKH6 which blocks kallikrein-kininogen complex formation with an IC 50 of 8 nM mapped to the center portion of domain A2. Our data indicate that domain A2 and two flanking sequence segments of A1 and A4 form a discontinuous binding platform for H-kininogen on the prekallikrein heavy chain. Domain-specific antibodies directed to these critical sites efficiently interfered with contact phase-induced bradykinin release from H-kininogen.

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A Binding Site for Heparin in the Apple 3 Domain of Factor XI

Cited by 82 publications

References 42 publications

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation

The Role of High Molecular Weight Kininogen and Prothrombin as Cofactors in the Binding of Factor XI A3 Domain to the Platelet Surface

Mapping of the Discontinuous H-kininogen Binding Site of Plasma Prekallikrein

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