Factor XI Interacts with the Leucine-rich Repeats of Glycoprotein Ibα on the Activated Platelet

Baglia, Frank A.; Shrimpton, Corie N.; Emsley, Jonas; Kitagawa, Kouki; Ruggeri, Zaverio M.; López, José A.; Walsh, Peter N.

doi:10.1074/jbc.m407889200

Cited by 74 publications

(65 citation statements)

References 44 publications

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“…Furthermore, GPIb-V-IX binds with high affinity to thrombin, which can support thrombin-induced activation of the receptors PAR1 and PAR4, although the physiological importance of the GPIb pathway is debated (68). In addition, GPIb␣ has been reported to bind the coagulation factors FXI, FXII, and high-molecular-weight kininogen (7) and may also function as a coreceptor for FVIIa (314) and FXI(a) (17). On the other hand, recent findings suggest that FXI binds to platelets via the receptor LRP8 (ApoeER2) (317).…”

Section: A Platelet Leucine-rich Repeat and Immunoglobulin Family Rementioning

confidence: 99%

New Fundamentals in Hemostasis

Versteeg

Heemskerk

Levi

et al. 2013

Physiological Reviews

912

831

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Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, while the second important component starts with platelet activation, which not only contributes to the hemostatic plug, but also accelerates the coagulation system. Eventually, coagulation and platelet activation are switched off by blood-borne inhibitors and proteolytic feedback loops. This review summarizes new concepts of activation of proteases that regulate coagulation and anticoagulation, to give rise to transient thrombin generation and fibrin clot formation. It further speculates on the (patho)physiological roles of intra-and extravascular receptors that operate in response to these proteases. Furthermore, this review provides a new framework for understanding how signaling and adhesive interactions between endothelial cells, leukocytes, and platelets can regulate thrombus formation and modulate the coagulation process. Now that the key molecular players of coagulation and platelet activation have become clear, and their complex interactions with the vessel wall have been mapped out, we can also better speculate on the causes of thrombosis-related angiopathies.

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Section: A Platelet Leucine-rich Repeat and Immunoglobulin Family Rementioning

confidence: 99%

New Fundamentals in Hemostasis

Versteeg

Heemskerk

Levi

et al. 2013

Physiological Reviews

912

831

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“…[2][3][4] Each subunit has 607 amino acids, with four 90-amino acid apple domains (A1-A4) that, in the FXI monomer, assemble into a saucer-shaped disc, with the protease domain resting on top in an arrangement that we have described as a cup and saucer. 5 Biochemical data have mapped protein interactions to the apple domains for diverse ligands, including substrate FIX, 6 thrombin, 7 platelet glycoprotein Ib, 8 and high-molecular-weight kininogen (HK), 9 but to date, no complex crystal structures have been determined to define the molecular basis of these interactions. 10 FXI circulates in complex with cofactor HK.…”

Section: Introductionmentioning

confidence: 99%

A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

Wong

Østergaard

Hall

et al. 2016

Blood

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Key Points• A novel FXI binding tripeptide motif has sequence Asp-PhePro (DFP).• FXI complex crystal structures reveal DFP peptides bound to the apple 2 domain.Factor XI (FXI) is the zymogen of FXIa, which cleaves FIX in the intrinsic pathway of coagulation. FXI is known to exist as a dimer and interacts with multiple proteins via its 4 apple domains in the "saucer section" of the enzyme; however, to date, no complex crystal structure has been described. To investigate protein interactions of FXI, a large random peptide library consisting of 10 6 to 10 7 peptides was screened for FXI binding, which identified a series of FXI binding motifs containing the signature Asp-Phe-Pro (DFP) tripeptide. Motifs containing this core tripeptide were found in diverse proteins, including the known ligand high-molecular-weight kininogen (HK), as well as the extracellular matrix proteins laminin and collagen V. To define the binding site on FXI, we determined the crystal structure of FXI in complex with the HK-derived peptide NPISDFPDT. This revealed the location of the DFP peptide bound to the FXI apple 2 domain, and central to the interaction, the DFP phenylalanine side-chain inserts into a major hydrophobic pocket in the apple 2 domain and the isoleucine occupies a flanking minor pocket. Two further structures of FXI in complex with the laminin-derived peptide EFPDFP and a DFP peptide from the random screen demonstrated binding in the same pocket, although in a slightly different conformation, thus revealing some flexibility in the molecular interactions of the FXI apple 2 domain. (Blood. 2016;127(23):2915-2923

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“…However recent observations cast considerable doubt on the conclusion that activated platelets can promote the feedback activation of FXI by thrombin (35)(36)(37). Therefore, in a revised model of the interactions of FXI and FXIa with the activated platelet surface (Figure 7), dimeric FXI in complex with either HK or prothrombin is shown to expose a site within the A3 domain that binds to glycoprotein Ibα on the activated platelet surface (12)(13)(14)(15)19). Since this interaction has been demonstrated to be reversible (13), and since it has not been rigorously demonstrated whether it is the plateletbound or soluble form of FXI that is converted to FXIa, the activation of FXI by FXIIa, FXIa or thrombin is shown in Figure 7 to occur in solution.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, neither resting nor thrombin-activated human umbilical vein endothelial cells have any capacity to bind FXI or promote its activation by thrombin (18). It has been demonstrated that the platelet membrane receptor for FXI consists of the glycoprotein Ib-IX-V complex (19).…”

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confidence: 99%

A Catalytic Domain Exosite (Cys⁵²⁷−Cys⁵⁴²) in Factor XIa Mediates Binding to a Site on Activated Platelets

et al. 2007

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The zymogen, factor XI, and the enzyme, factor XIa, interact specifically with functional receptors on the surface of activated platelets. The present studies were initiated to identify the molecular subdomain within factor XIa that binds to activated platelets. Both factor XIa (K i ~1.4 nM) and a chimeric factor XIa containing the Apple 3 domain of prekallikrein (K i ~2.7 nM) competed with 125 I-factor XIa for binding sites on activated platelets suggesting that the factor XIa binding site for platelets is not located in the Apple 3 domain which mediates factor XI binding to platelets. The recombinant catalytic domain (Ile 370 -Val 607 ) inhibited the binding of 125 I-factor XIa to the platelets (K i ~3.5 nM) whereas the recombinant factor XI heavy chain did not demonstrating that the platelet binding site is located in the light chain of factor XIa. A conformationally constrained cyclic peptide (Cys 527 -Cys 542 ) containing a high-affinity (K D ~86 nM) heparin-binding site within the catalytic domain of factor XIa also displaced 125 I-factor XIa from the surface of activated platelets (K i ~5.8 nM), whereas a scrambled peptide of identical composition was without effect suggesting that the binding site in factor XIa that interacts with the platelet surface resides in the catalytic domain near the heparin binding site of factor XIa. These data support the conclusion that a conformational transition accompanies conversion of factor XI to factor XIa that conceals the Apple 3 domain factor XI (zymogen) platelet binding site and exposes the factor XIa (enzyme) platelet binding site within the catalytic domain possibly comprising residues Cys 527 -Cys 542 . KeywordsFactor XIa; Platelet Receptors; Factor XI; Catalytic Domain Exosites; Apple Domains Factor XI (FXI) 1 is a homodimeric plasma coagulation protein (1-4), deficiency of which produces a mild hemostatic defect associated with trauma or surgery (5-8), in contrast to deficiencies of the "contact factors" (Factor XII [FXII], prekallikrein [PK], and high molecular † This work is supported by research grants from the National Institute of Health: (HL74124 and HL46213 to PNW and from the American Heart Association (99100069U to TRB). *To Whom Correspondence Should be Addressed: Peter N. Walsh, M.D., Ph.D., Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140; Tel.: 215-707-4375; Fax: 215-707-3005; E-mail: pnw@temple.edu. 1 Abbrevations used: FXI, factor XI; FXIa, factor XIa; FXII, factor XII; FXIIa, factor XIIa; PK, prekallikrein; HK, high molecular weight kininogen; A3, Apple 3; FIX, factor IX; FIXa, factor IXa; PN2, protease nexin 2; pFXIa, plasma FXIa; rFXI/PKA3, recombinant FXI with the A3 domain of FXI replaced with the A3 of PK; rFXIa/C362S,C482S, recombinant FXI with cysteine 362 and cysteine 482 mutated to serines; rFXIac, factor XIa catalytic domain; TRAP, thrombin receptor activation peptide.

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Factor XI Interacts with the Leucine-rich Repeats of Glycoprotein Ibα on the Activated Platelet

Cited by 74 publications

References 44 publications

New Fundamentals in Hemostasis

New Fundamentals in Hemostasis

A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

A Catalytic Domain Exosite (Cys⁵²⁷−Cys⁵⁴²) in Factor XIa Mediates Binding to a Site on Activated Platelets

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Factor XI Interacts with the Leucine-rich Repeats of Glycoprotein Ibα on the Activated Platelet

Cited by 74 publications

References 44 publications

New Fundamentals in Hemostasis

New Fundamentals in Hemostasis

A novel DFP tripeptide motif interacts with the coagulation factor XI apple 2 domain

A Catalytic Domain Exosite (Cys527−Cys542) in Factor XIa Mediates Binding to a Site on Activated Platelets

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A Catalytic Domain Exosite (Cys⁵²⁷−Cys⁵⁴²) in Factor XIa Mediates Binding to a Site on Activated Platelets