Kallikrein Cleaves C3 and Activates Complement

Irmscher, Sarah; Döring, Nadia; Halder, Luke D.; Eah, Jo; Kopka, Isabell; Dunker, C; Jacobsen, Ilse D.; Luo, Sanzhong; Slevogt, Hortense; Lorkowski, Stefan; Beyersdorf, Niklas; Pf, Zipfel; Skerka, Christine

doi:10.1159/000484257

Cited by 95 publications

(78 citation statements)

References 41 publications

(51 reference statements)

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“…The regulation of extracellular proteolysis is critical to blood hemostasis and innate immunity and proteases plasma prekallikrein (PK), and coagulation factors XII (FXII) and XI (FXI) act as master regulators of several cascades including coagulation, fibrinolysis, complement activation, and inflammation . PK is an unusual plasma protease as it does not recruit its principal substrate high‐molecular‐weight kininogen (HK) upon activation but rather it circulates as a zymogen in a tightly bound but inactive PK‐HK complex , raising the question as to how this complex is effectively regulated.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Properdin can also bind, and subsequently stabilize, C3 convertase in the alternative pathway [22]. Studies have shown that the alternative pathway is initiated by not only properdin but also various proteases, including thrombin and kallikrein [24][25][26].…”

Section: Complement Systemmentioning

confidence: 99%

Kaposi’s Sarcoma-Associated Herpesvirus and Host Interaction by the Complement System

Yoo

Lee

2020

Pathogens

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Kaposi’s sarcoma-associated herpesvirus (KSHV) modulates the immune response to allow the virus to establish persistent infection in the host and facilitate the development of KSHV-associated cancer. The complement system has a central role in the defense against pathogens. Hence, KSHV has adopted an evasion strategy for complement attack using the viral protein encoded by KSHV open reading frame 4. However, despite this defense mechanism, the complement system appears to become activated in KSHV-infected cells as well as in the region surrounding Kaposi’s sarcoma tumors. Given that the complement system can affect cell fate as well as the inflammatory microenvironment, complement activation is likely associated with KSHV pathogenesis. A better understanding of the interplay between KSHV and the complement system may, therefore, translate into the development of novel therapeutic interventions for KSHV-associated tumors. In this review, the mechanisms and functions of complement activation in KSHV-infected cells are discussed.

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“…A further link between the contact system and host defense is activation of the alternative complement pathway by FXII that triggers activation of the C1 complex ( 31 ). In the alternative complement pathway, PK can replace factor D for the activation of C3 convertase ( 32 , 33 ). Simultaneous activation of the contact and complement system results in the generation of nascent molecules that have significant impact in various in inflammatory diseases including angioedema and cancer ( 34 ).…”

Section: The Pro-inflammatory Kallikrein–kinin System As a Link To Inmentioning

confidence: 99%

Interaction of the Human Contact System with Pathogens—An Update

Oehmcke-Hecht

Köhler

2018

Front. Immunol.

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The name human contact system is related to its mode of action, as “contact” with artificial negatively charged surfaces triggers its activation. Today, it is generally believed that the contact system is an inflammatory response mechanism not only against artificial material but also against misfolded proteins and foreign organisms. Upon activation, the contact system is involved in at least two distinct (patho)physiologic processes:i. the trigger of the intrinsic coagulation via factor XI and ii. the cleavage of high molecular weight kininogen with release of bradykinin and antimicrobial peptides (AMPs). Bradykinin is involved in the regulation of inflammatory processes, vascular permeability, and blood pressure. Due to the release of AMPs, the contact system is regarded as a branch of the innate immune defense against microorganisms. There is an increasing list of pathogens that interact with contact factors, in addition to bacteria also fungi and viruses bind and activate the system. In spite of that, pathogens have developed their own mechanisms to activate the contact system, resulting in manipulation of this host immune response. In this up-to-date review, we summarize present research on the interaction of pathogens with the human contact system, focusing particularly on bacterial and viral mechanisms that trigger inflammation via contact system activation.

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Kallikrein Cleaves C3 and Activates Complement

Cited by 95 publications

References 41 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

Kaposi’s Sarcoma-Associated Herpesvirus and Host Interaction by the Complement System

Interaction of the Human Contact System with Pathogens—An Update

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