Role of MASP-3 in the Physiological Activation of Factor D of the Alternative Complement Pathway
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MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity 1
MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity 1 József Dobó 2,3* , Veronika Harmat 3† , László Beinrohr *, Edina Sebestyén *, Péter Závodszky *, Péter Gál 2* * Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Karolina út 29, H-1113, Budapest, Hungary † Protein Modeling Group, Hungarian Academy of Sciences, and Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University , Pázmány Péter sétány 1A, H-1117, Budapest, Hungary Running title: Structure of MASP-1 CCP1-CCP2-SP Keywords (not in the title): lectin pathway; innate immunity; modular serine protease; mannan-binding lectin; MBL-associated serine protease; MASP-2; C1r; C1s; thrombin; trypsin; factor D 1 Abstract Mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) is an abundant component of the lectin pathway of complement. The related enzyme, MASP-2 is capable of activating the complement cascade alone. Though the concentration of MASP-1 far exceeds that of MASP-2 only a supporting role of MASP-1 has been identified regarding lectin pathway activation. Several non-complement substrates, like fibrinogen and factor XIII, have also been reported. MASP-1 belongs to the C1r/C1s/MASP family of modular serine proteases, however its serine protease domain is evolutionary different. We have determined the crystal structure of the catalytic region of active MASP-1 and refined it to 2.55 Å resolution. Unusual features of the structure are: an internal salt bridge (similar to one in factor D) between the S1 Asp189 and Arg224, and a very long 60-loop. -
WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T (51) International Patent Classification: (71) Applicant: RESVERLOGIX CORP. [CA/CA]; 300, A61K 31/551 (2006.01) A61P 37/02 (2006.01) 4820 Richard Road Sw, Calgary, AB, T3E 6L1 (CA). A61K 31/517 (2006.01) C07D 239/91 (2006.01) (72) Inventors: WASIAK, Sylwia; 431 Whispering Water (21) International Application Number: Trail, Calgary, AB, T3Z 3V1 (CA). KULIKOWSKI, PCT/IB20 16/000443 Ewelina, B.; 31100 Swift Creek Terrace, Calgary, AB, T3Z 0B7 (CA). HALLIDAY, Christopher, R.A.; 403 (22) International Filing Date: 138-18th Avenue SE, Calgary, AB, T2G 5P9 (CA). GIL- 10 March 2016 (10.03.2016) HAM, Dean; 249 Scenic View Close NW, Calgary, AB, (25) Filing Language: English T3L 1Y5 (CA). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/132,572 13 March 2015 (13.03.2015) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/264,768 8 December 2015 (08. 12.2015) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [Continued on nextpage] (54) Title: COMPOSITIONS AND THERAPEUTIC METHODS FOR THE TREATMENT OF COMPLEMENT-ASSOCIATED DISEASES (57) Abstract: The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders as sociated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof. -
Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E. -
By Map44 Pathway Activation in a Manner Inhibitable Pattern
Co-Complexes of MASP-1 and MASP-2 Associated with the Soluble Pattern-Recognition Molecules Drive Lectin Pathway Activation in a Manner Inhibitable This information is current as by MAp44 of September 28, 2021. Søren E. Degn, Lisbeth Jensen, Tomasz Olszowski, Jens C. Jensenius and Steffen Thiel J Immunol 2013; 191:1334-1345; Prepublished online 19 June 2013; Downloaded from doi: 10.4049/jimmunol.1300780 http://www.jimmunol.org/content/191/3/1334 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/06/19/jimmunol.130078 Material 0.DC1 References This article cites 43 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/191/3/1334.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Co-Complexes of MASP-1 and MASP-2 Associated with the Soluble Pattern-Recognition Molecules Drive Lectin Pathway Activation in a Manner Inhibitable by MAp44 Søren E. -
Crystal Structure of Prethrombin-1
Crystal structure of prethrombin-1 Zhiwei Chen, Leslie A. Pelc, and Enrico Di Cera1 Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104 Edited by Robert M. Stroud, University of California, San Francisco, CA, and approved September 24, 2010 (received for review July 14, 2010) Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from pro- thrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156–271), A chain (residues 272–320), and B chain (re- sidues 321–579). The X-ray crystal structure of prethrombin-1 solved at 2.2-Å resolution shows an overall conformation signifi- cantly different (rmsd ¼ 3.6 Å) from that of its active form meizo- thrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the y axis by 29° and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Naþ binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 Å apart in mei- zothrombin desF1, to come within 3.3 Å of each other and comple- tely occlude access to the active site. -
Factor B, the Complement Alternative Pathway Serine Proteinase, Is a Major Constitutive Protein Synthesized and Secreted by Resident and Elicited Mouse Macrophages
FACTOR B, THE COMPLEMENT ALTERNATIVE PATHWAY SERINE PROTEINASE, IS A MAJOR CONSTITUTIVE PROTEIN SYNTHESIZED AND SECRETED BY RESIDENT AND ELICITED MOUSE MACROPHAGES BY JOHN S. SUNDSMO, JENNIE R. CHIN,* RUTH A. PAPIN, DARYL S. FAIR, AND ZENA WERB* From the Department of Molecular Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037; and the *Laboratory of Radiobiology and Environmental Health, and Department of Anatomy, University of California, San Francisco, California 94143 Mononuclear phagocytes have been increasingly recognized as a source of many of the complement proteins (1, 2). Activities constituting the intact com- plement alternative pathway in serum (factor B, factor D, C3, and properdin) (3-8), as well as the regulatory proteins, factors H and I (5, 8), are produced by mouse peritoneal macrophages and human peripheral blood monocytes. Factors C2 and C4 are also synthesized by mononuclear phagocytes (1, 2, 5, 9-11). Factor B, a glycoprotein of Mr ~0.3,000 that plays a central role in the alternative pathway of complement activation (12, 13), is closely associated with the immune response as a class III gene product of the major histocompatibility complex in mice (14, 15), guinea pigs (16), and humans (17). Activated factor B (Bb, Mr ~60,000) serves as a migration inhibiting factor (18), inducing macro- phage and monocyte spreading (19, 20) and possibly stimulating cytotoxic (21, 22) and bacteriocidai activities (23, 24) of monocytes in vitro. The hemolytic activity of factor B produced by resident mouse peritoneal macrophages (3, 6) increases linearly during 72-96 h in culture, and its synthesis is regulated by lipopolysaccharide (LPS) 1 (24). -
Ncounter Human Inflammation V2 Panel Gene List
nCounter Human Inflammation V2 Panel Gene List Official Symbol Accession Alias / Prev Symbol GO Annotation* Official Full Name Intrinsic To Plasma Membrane,Intrinsic To Membrane,Membrane Part,Membrane,Integral To Membrane,Integral To Plasma Membrane,Plasma Membrane Part,Plasma Membrane,Signal Transduction,Cell Surface Receptor Linked Signal Transduction Go 0007166,Defense Response,Inflammatory Response,Response To Stress,Response To External AGER NM_001136.3 RAGE Stimulus,Response To W advanced glycosylation end product-specific receptor Cytoplasmic Part,Membrane,Cytoplasm,Cytosol,Plasma Membrane,Regulation Of Biological Quality,Positive Regulation Of Cell Proliferation,Cell Development,Negative Regulation Of Apoptosis,Programmed Cell Death,Regulation Of Growth,Carboxylic Acid Metabolic ALOX12 NM_000697.1 12-LOX, 12S-LOX, LOG12 Process,Fatty Acid Oxidation,Negative Regulation Of Cellular Process,Regulation Of Cell arachidonate 12-lipoxygenase Defense Response,Inflammatory Response,Response To Stress,Response To External ALOX15 NM_001140.3 15-LOX-1, 15LOX-1 Stimulus,Response To Wounding,Oxidoreductase Activity arachidonate 15-lipoxygenase ALOX5 NM_000698.2 5-LO, 5-LOX, 5LPG, LOG5 Oxidoreductase Activity arachidonate 5-lipoxygenase Extracellular Region,Extracellular Region Part,Extracellular Space,Cell Cell Signaling,Cell AREG NM_001657.2 AR, CRDGF, SDGF Proliferation Go 0008283,Receptor Binding,Growth Factor Activity amphiregulin Cytoplasm,Carboxylic Acid Metabolic Process,Glutamine Family Amino Acid Metabolic Process,Amino Acid Metabolic -
Factor B Catalog Number
Name: Factor B Catalog Number: A135 Sizes Available: 250 µg/vial Concentration: 1.0 mg/mL (see Certificate of Analysis for actual concentration) Form: Frozen liquid Activity: >90% versus normal human serum standard. Purity: >95% by SDS-PAGE Buffer: 10 mM Sodium phosphate, 145 mM NaCl, pH 7.2 Molecular weight: 93,000 Da (single chain) Extinction Coeff.: A280 nm = 1.27 at 1.0 mg/mL Preservative: None, 0.22 µm filtered Storage: -70oC or below. Avoid repeated freeze/thaw. Source: Normal human serum (shown by certified tests to be negative for HBsAg and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Origin: Manufactured in the USA. General Description Complement factor B (fB) is purified from normal human serum. Complement factor B is a glycosylated protein composed of a single 93,000 Da polypeptide chain. It is an essential component of the alternative pathway of complement activation and is found in plasma at approximately 200 µg/mL. In the presence of Mg++ factor B binds to C3b and the C3b,B complex can be activated by factor D, a serine protease that circulates as an active trypsin-like serine protease. Cleavage of factor B by factor D causes the release of the Ba fragment (33,000 Da) and leaves the 60,000 Bb fragment bound to C3b. This Bb subunit is a serine protease. C3b,Bb is called a C3 and a C5 convertase because it converts both of these proteins to their active forms by cleaving off the small peptides C3a and C5a, respectively (Morikis, D. -
Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................ -
Complement Activation in Factor D-Deficient Mice
Complement activation in factor D-deficient mice Yuanyuan Xu*†, Minghe Ma‡, Gregory C. Ippolito*, Harry W. Schroeder, Jr.*, Michael C. Carroll‡, and John E. Volanakis*§ *Department of Medicine, University of Alabama, Birmingham, AL 35294; ‡Department of Pathology, Harvard Medical School, Boston, MA 02138; and §Biomedical Sciences Research Center ‘‘A. Fleming,’’ Vari 166 72, Greece Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 18, 2001 (received for review August 15, 2001) To assess the contribution of the alternative pathway in comple- mice. The results indicate that factor D is indispensable for ment activation and host defense and its possible role in the complement activation through the AP and that it plays a regulation of systemic energy balance in vivo, factor D-deficient significant role in opsonization of bacteria by ‘‘natural’’ IgM mice were generated by gene targeting. The mutant mice have no antibody. It is also shown that factor D does not play a major role apparent abnormality in development and their body weights are in fat metabolism. Interestingly, the data revealed a unique mode similar to those of factor D-sufficient littermates. Complement of factor B activation, which provides valuable insights into the activation could not be initiated in the serum of deficient mice by mechanism of AP activation. the alternative pathway activators rabbit erythrocytes and zymo- san. Surprisingly, injection of cobra venom factor (CVF) caused a Materials and Methods profound and reproducible reduction in serum C3 levels, whereas, Generation of Factor D-Deficient Mice. A gene targeting vector, as expected, there was no C3 reduction in factor B-deficient mice Adn͞TK, was constructed (9) on the backbone of pBluescript treated similarly. -
MASP-3 Is the Exclusive Pro-Factor D Activator in Resting Blood: the Lectin and the Alternative Complement Pathways Are Fundamentally Linked
www.nature.com/scientificreports OPEN MASP-3 is the exclusive pro- factor D activator in resting blood: the lectin and the alternative Received: 03 May 2016 Accepted: 29 July 2016 complement pathways are Published: 18 August 2016 fundamentally linked József Dobó1,*, Dávid Szakács2,*, Gábor Oroszlán1, Elod Kortvely3, Bence Kiss2, Eszter Boros2, Róbert Szász4, Péter Závodszky1, Péter Gál1 & Gábor Pál2 MASP-3 was discovered 15 years ago as the third mannan-binding lectin (MBL)-associated serine protease of the complement lectin pathway. Lacking any verified substrate its role remained ambiguous. MASP-3 was shown to compete with a key lectin pathway enzyme MASP-2 for MBL binding, and was therefore considered to be a negative complement regulator. Later, knock-out mice experiments suggested that MASP-1 and/or MASP-3 play important roles in complement pro-factor D (pro-FD) maturation. However, studies on a MASP-1/MASP-3-deficient human patient produced contradicting results. In normal resting blood unperturbed by ongoing coagulation or complement activation, factor D is present predominantly in its active form, suggesting that resting blood contains at least one pro-FD activating proteinase that is not a direct initiator of coagulation or complement activation. We have recently showed that all three MASPs can activate pro-FD in vitro. In resting blood, however, using our previously evolved MASP-1 and MASP-2 inhibitors we proved that neither MASP-1 nor MASP-2 activates pro-FD. Other plasma proteinases, particularly MASP-3, remained candidates for that function. For this study we evolved a specific MASP-3 inhibitor and unambiguously proved that activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways. -
Innate Immunity: the Inside Story on Complement Activation
RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis.