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

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          Abstract

          Essentials

          • 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
          Background

          Plasma 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.

          Objective

          To investigate the three‐dimensional structure of full‐length PKa and perform a comparison with FXI.

          Methods

          A series of recombinant full‐length PKa and FXI constructs and variants were developed and the crystal structures determined.

          Results and conclusions

          A 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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          Most cited references38

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          Knowledge-based protein secondary structure assignment.

          We have developed an automatic algorithm STRIDE for protein secondary structure assignment from atomic coordinates based on the combined use of hydrogen bond energy and statistically derived backbone torsional angle information. Parameters of the pattern recognition procedure were optimized using designations provided by the crystallographers as a standard-of-truth. Comparison to the currently most widely used technique DSSP by Kabsch and Sander (Biopolymers 22:2577-2637, 1983) shows that STRIDE and DSSP assign secondary structural states in 58 and 31% of 226 protein chains in our data sample, respectively, in greater agreement with the specific residue-by-residue definitions provided by the discoverers of the structures while in 11% of the chains, the assignments are the same. STRIDE delineates every 11th helix and every 32nd strand more in accord with published assignments.
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            Contact system revisited: an interface between inflammation, coagulation, and innate immunity.

            The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy-associated increase in bleeding, renewing interest in the FXIIa-driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross-road of inflammation, coagulation, and innate immunity.
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              Structure and function of factor XI.

              Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K-dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 "apple domains" that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.
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                Author and article information

                Contributors
                jonas.emsley@nottingham.ac.uk
                Journal
                J Thromb Haemost
                J. Thromb. Haemost
                10.1111/(ISSN)1538-7836
                JTH
                Journal of Thrombosis and Haemostasis
                John Wiley and Sons Inc. (Hoboken )
                1538-7933
                1538-7836
                19 March 2019
                May 2019
                : 17
                : 5 ( doiID: 10.1111/jth.2019.17.issue-5 )
                : 759-770
                Affiliations
                [ 1 ] Centre for Biomolecular Sciences School of Pharmacy University of Nottingham Nottingham UK
                [ 2 ] Aflac Cancer and Blood Disorders Center Department of Pediatrics Emory University School of Medicine Atlanta GA USA
                [ 3 ] Departments of Hematology and Oncology and Cellular and Molecular Medicine Cleveland Clinic Cleveland OH USA
                Author notes
                [*] [* ] Correspondence: Jonas Emsley, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK

                Tel.: +44 115 846 7092

                E‐mail: jonas.emsley@ 123456nottingham.ac.uk

                Author information
                https://orcid.org/0000-0003-2256-642X
                https://orcid.org/0000-0002-5806-5080
                https://orcid.org/0000-0002-8949-8030
                Article
                JTH14418
                10.1111/jth.14418
                6899681
                30801944
                3a2617aa-b240-4dd6-bf1d-31ab0ca60fce
                © 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 January 2019
                Page count
                Figures: 5, Tables: 1, Pages: 12, Words: 6967
                Funding
                Funded by: British Heart Foundation , open-funder-registry 10.13039/501100000274;
                Award ID: RG/12/9/29775
                Categories
                Original Article
                THROMBOSIS
                Original Articles
                Custom metadata
                2.0
                May 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                Hematology
                factor ix,factor xi,factor xii,kininogens,plasma kallikrein
                Hematology
                factor ix, factor xi, factor xii, kininogens, plasma kallikrein

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