Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI

Pathak, Monika; Kaira, Bubacarr G; Slater, Alexandre; Emsley, Jonas

doi:10.3389/fmed.2018.00066

Cited by 13 publications

(13 citation statements)

References 162 publications

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“…The cleavage of extracellular matrix proteins by PKa has also been described in the astrocyte secretome although the precise location of the cleavage sites and involvement of the apple domains in substrate selection remains unknown . The interaction of PK and FXI with cell receptors has been characterized and the apple domains have been reported to be implicated although the precise binding sites remain unknown .…”

Section: Discussionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

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Zymogen PK is activated to PKa and cleaves substrates kininogen and FXII contributing to bradykinin generation. Monomeric PKa and dimeric homologue FXI utilize the N‐terminal apple domains to recruit substrates. A high‐resolution 1.3 Å structure of full‐length PKa reveals an active conformation of the protease and apple domains. The PKa protease and four‐apple domain disc organization is 180° rotated compared to FXI. Summary BackgroundPlasma prekallikrein (PK) and factor XI (FXI) are apple domain‐containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin release, inflammation, and thrombosis pathways. ObjectiveTo investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI. MethodsA series of recombinant full‐length PKa and FXI constructs and variants were developed and the crystal structures determined. Results and conclusionsA 1.3 Å structure of full‐length PKa reveals the protease domain positioned above a disc‐shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulfide and structural differences in the apple 4 domain that prevents dimer formation in PK as opposed to FXI. Two latchlike loops (LL1 and LL2) extend from the PKa protease domain to form interactions with the apple 1 and apple 3 domains, respectively. A major unexpected difference in the PKa structure compared to FXI is the 180° disc rotation of the apple domains relative to the protease domain. This results in a switched configuration of the latch loops such that LL2 interacts and buries portions of the apple 3 domain in the FXI zymogen whereas in PKa LL2 interacts with the apple 1 domain. Hydrogen‐deuterium exchange mass spectrometry on plasma purified human PK and PKa determined that regions of the apple 3 domain have increased surface exposure in PKa compared to the zymogen PK, suggesting conformational change upon activation.

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Section: Discussionmentioning

confidence: 99%

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Voos

Pathak

et al. 2019

Journal of Thrombosis and Haemostasis

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“…FXIIa activates FXI to FXIa and triggers the intrinsic pathway of the coagulation cascade through the subsequent activation of FIX, FX, and prothrombin. FXIIa‐induced activation of PKa also results in cleavage of HK to release the vasoactive substance bradykinin, which leads to endothelial permeability, leukocyte recruitment, and cytokine generation …”

Section: The Contact Activation System In Sepsismentioning

confidence: 96%

“…The CAS is activated upon blood exposure to an increasing number of recognized substances, including negatively charged artificial surfaces, various infectious pathogens, long‐chain polyphosphates (polyPs), and cell‐free DNA/RNA. In sepsis in particular, CAS activation seems to be triggered by contact with negatively charged surfaces, including platelet‐derived polyP and bacterial cell components such as peptidoglycans, teichoic acid, and lipopolysaccharide . Upon exposure to an activating surface, FXII changes conformation to become the serine protease FXIIa.…”

Section: The Contact Activation System In Sepsismentioning

confidence: 99%

The contact pathway and sepsis

Raghunathan

Zilberman‐Rudenko

Olson

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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The contact pathway factors XI (FXI) and XII (FXII) have been demonstrated to be largely dispensable for hemostasis, as their absence results in a mild to absent bleeding diathesis. A growing body of literature, however, suggests that the contact pathway contributes to the pathologic host response to certain infectious organisms that produces the often‐fatal syndrome known as sepsis. The contact pathway factors serve as a central node connecting inflammation to coagulation, and may offer a potentially safe therapeutic target to mitigate the morbidity and mortality associated with sepsis. Herein, we summarize published in vivo and in vitro data that have explored the roles of the contact pathway in sepsis, and discuss potential clinical applications of novel FXI‐ and FXII‐inhibiting drugs currently under investigation.

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“…BK, a short-lived bioactive peptide 35 , is the terminal product of CSA cascade. Given that the entire BK-forming cascade can be assembled and activated along the surface of endothelial cells 36 , 37 , HUVEC were incubated with standard human plasma and then the plasma was removed. The obtained PI-HUVEC, which had combined all elements for BK generation, could be used for the measurement of BK in vitro.…”

Section: Resultsmentioning

confidence: 99%

Penicillin causes non-allergic anaphylaxis by activating the contact system

Gao

Han

Zhang

et al. 2020

Sci Rep

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Immediate hypersensitivity reaction (IHR) can be divided into allergic- and non-allergic-mediated, while “anaphylaxis” is reserved for severe IHR. Clinically, true penicillin allergy is rare and most reported penicillin allergy is “spurious”. Penicillin-initiated anaphylaxis is possible to occur in skin test- and specific IgE-negative patients. The contact system is a plasma protease cascade initiated by activation of factor XII (FXII). Many agents with negative ion surface can activate FXII to drive contact system. Our data showed that penicillin significantly induced hypothermia in propranolol- or pertussis toxin-pretreated mice. It also caused a rapid and reversible drop in rat blood pressure, which did not overlap with IgE-mediated hypotension. These effects could be countered by a bradykinin-B2 receptor antagonist icatibant, and consistently, penicillin indeed increased rat plasma bradykinin. Moreover, penicillin not only directly activated contact system FXII-dependently, but also promoted bradykinin release in plasma incubated-human umbilical vein endothelial cells. In fact, besides penicillin, other beta-lactams also activated the contact system in vitro. Since the autoactivation of FXII can be affected by multiple-factors, plasma from different healthy individuals showed vastly different amidolytic activity in response to penicillin, suggesting the necessity of determining the potency of penicillin to induce individual plasma FXII activation. These results clarify that penicillin-initiated non-allergic anaphylaxis is attributed to contact system activation, which might bring more effective diagnosis options for predicting penicillin-induced fatal risk and avoiding costly and inappropriate treatment clinically.

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Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI

Cited by 13 publications

References 162 publications

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI

The contact pathway and sepsis

Penicillin causes non-allergic anaphylaxis by activating the contact system

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