DOCSLIB.ORG

Protein, and Associates with Lipoprotein Activity, Binds Heparin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Protein, and Associates with Lipoprotein Activity, Binds Heparin Human Factor H-Related Protein 5 Has Cofactor Activity, Inhibits C3 Convertase Activity, Binds Heparin and C-Reactive Protein, and Associates with Lipoprotein This information is current as of October 1, 2021. Jennifer L. McRae, Thomas G. Duthy, Kim M. Griggs, Rebecca J. Ormsby, Peter J. Cowan, Brett A. Cromer, William J. McKinstry, Michael W. Parker, Brendan F. Murphy and David L. Gordon J Immunol 2005; 174:6250-6256; ; Downloaded from doi: 10.4049/jimmunol.174.10.6250 http://www.jimmunol.org/content/174/10/6250 References This article cites 48 articles, 30 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/174/10/6250.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Factor H-Related Protein 5 Has Cofactor Activity, Inhibits C3 Convertase Activity, Binds Heparin and C-Reactive Protein, and Associates with Lipoprotein1 Jennifer L. McRae,2*†‡Thomas G. Duthy,§ Kim M. Griggs,§ Rebecca J. Ormsby,§ Peter J. Cowan,†‡ Brett A. Cromer,¶ William J. McKinstry,¶ Michael W. Parker,¶ Brendan F. Murphy,*†‡ and David L. Gordon§ Factor H-related protein 5 (FHR-5) is a recently discovered member of the factor H (fH)-related protein family. FHR proteins are structurally similar to the complement regulator fH, but their biological functions remain poorly defined. FHR-5 is synthesized in the liver and consists of 9 short consensus repeats (SCRs), which display various degrees of homology to those of fH and the other FHR proteins. FHR-5 colocalizes with complement deposits in vivo and binds C3b in vitro, suggesting a role in complement Downloaded from regulation or localization. The current study examined whether rFHR-5 exhibits properties similar to those of fH, including heparin binding, CRP binding, cofactor activity for the factor I-mediated degradation of C3b and decay acceleration of the C3 convertase. rFHR-5 bound heparin-BSA and heparin-agarose and a defined series of truncations expressed in Pichia pastoris localized the heparin-binding region to within SCRs 5–7. rFHR-5 bound CRP, and this binding was also localized to SCRs 5–7. FHR-5 inhibited alternative pathway C3 convertase activity in a fluid phase assay; however, dissociation of the convertase was not observed in a solid phase assay. rFHR-5 displayed factor I-dependent cofactor activity for C3b cleavage, although it was appar- http://www.jimmunol.org/ ently less effective than fH. In addition, we demonstrate association of FHR-5 with high density lipid lipoprotein complexes in human plasma. These results demonstrate that FHR-5 shares properties of heparin and CRP binding and lipoprotein association with one or more of the other FHRs but is unique among this family of proteins in possessing independent complement-regulatory activity. The Journal of Immunology, 2005, 174: 6250–6256. actor H-related protein 5 (FHR-5)3 is a member of the Regions of fH responsible for binding glycosaminoglycans such as human factor H (fH) protein family (1). This family of heparin have previously been mapped to SCRs 7, 20, and possibly structurally and immunologically related proteins includes 12–14 (3–6), whereas C-reactive protein (CRP)-binding sites have F by guest on October 1, 2021 fH, fH-like protein 1, and five other FHR proteins denoted FHR-1, been localized to SCRs 7 and 8–11 (7). C3b-binding sites are -2, -3, -4A, and -4B. fH is a crucial negative regulator of the within SCRs 2–3, 6–10, and/or 12–14 and 19–20 (8, 9), and com- alternative pathway (AP) of complement activation and targets the plement-regulatory activities reside within SCRs 1–4 (10–12). C3 (C3bBb) and C5 (C3bBbC3b) convertases of the AP in three Little is known about the function of FHR-1 and FHR-2, which ways. It acts as a competitor for factor B binding to C3b to form contain 5 and 4 SCR domains respectively, but both are present in the convertases, is an essential cofactor for factor I-mediated deg- lipoprotein complexes (13–15). FHR-3 and FHR-4B are highly radation of C3b to iC3b, and it accelerates the decay of Bb from related and consist of five SCRs. FHR-4A contains nine SCRs and the C3/C5 convertases (for review, see Ref. 2). fH is a 150-kDa is also closely associated with human triglyceride-rich lipoproteins serum protein consisting of 20 short consensus repeats (SCRs) (16, 17). Despite their sequence similarity, only FHR-3 possesses each composed of ϳ60 aa with 2 overlapping disulfide bonds. heparin-binding activity. This is the likely consequence of FHR-3 possessing an SCR with homology to SCR 7 of fH (3). FHR-3 also *Department of Nephrology, †Immunology Research Centre, and ‡University of Mel- binds streptococcal M protein, an interaction also mediated via bourne Department of Medicine, St. Vincent’s Hospital Melbourne, Fitzroy, Victoria, SCR 7 of fH (18). Both FHR-3 and FHR-4B bind to the C3d region Australia; §Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Bedford Park, Australia; and ¶St. Vincent’s Institute, Fitzroy, Australia of C3b and have been reported to have weak factor I-mediated Received for publication January 14, 2004. Accepted for publication March 14, 2005. cofactor activity, although this activity is not independent of fH The costs of publication of this article were defrayed in part by the payment of page and remains controversial (19). charges. This article must therefore be hereby marked advertisement in accordance FHR-5 is a 65-kDa protein first identified as a component of with 18 U.S.C. Section 1734 solely to indicate this fact. pathological human glomerular preparations. Unlike the other 1 This work was supported by grants from the National Health and Medical Research Council of Australia. FHR proteins, which contain 4 or 5 SCRs, FHR-5 consists of 9 SCR domains. SCRs 1 and 2 are homologous to corresponding 2 Address correspondence and reprint requests to Corresponding author: Jennifer L. McRae, Immunology Research Centre, St. Vincent’s Hospital Melbourne, PO Box SCRs from FHR-1 and FHR-2, whereas SCRs 3–7 and 8–9 share 2900, Fitzroy, Victoria, 3065, Australia., Ph: 61 3 9288 3140. Fax: 61 3 9288 3151. significant homology with SCRs 10–14 and 19–20 of fH (1). The e-mail: [email protected] gene encoding FHR-5 has been localized to human chromosome 3 Abbreviations used in this paper: FHR-5, factor H-related protein 5; fH, factor H; FHR-1, fH-related protein 1; FHR-2, fH-related protein 2; FHR-3, fH-related protein 1q32 within the regulators of complement activation (RCA) gene 3; FHR-4, fH-related protein 4; AP, alternative pathway; SCR, short consensus repeat; cluster. It is closely linked to the other fH family genes and is CRP, C-reactive protein; RCA, regulators of complement activation; RT, room tem- perature; GVB, gelatin-Veronal buffer; LDL, low density lipoprotein; VLDL, very situated between FHR-2 and factor XIIIb. Each SCR of FHR-5 is low density lipoprotein; HDL, high density lipoprotein. encoded by an individual exon (20). Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 6251 Although the exact role of FHR-5 in complement regulation is bled, and the sera were tested by ELISA and Western blot for activity unknown, the protein has been shown to colocalize with C3 in vivo against rFHR-5 and normal human serum. and to bind C3b in vitro in a dose-dependent manner (1). Its dep- Western blot analysis osition in vivo appears widespread in complement-containing glo- merular immune deposits and extrarenal sites of complement dep- Recombinant FHR-5 SCR proteins and lipoprotein fractions were sepa- rated on 10–12% SDS-PAGE and transferred onto Hybond Cϩ nitrocel- osition (21). A prospective study of 100 renal biopsies showed the lulose (Amersham Biosciences). Native and rFHR-5 proteins were detected pattern of FHR-5 deposition to be similar to that of C3 and C5b-9 using rabbit anti-FHR-5 antiserum (1/2000 v/v) or mouse anti-FHR-5 (22). More recently, FHR-5 and all other FHR proteins have been (K2.254) mAb (Ref. 21; 1/2000 v/v) followed by HRP-conjugated goat detected at high levels in middle ear effusion fluid from patients anti-rabbit IgG (Silenus) or HRP-conjugated sheep anti-mouse IgG (Sile- with otitis media (23). nus) (1/2000 v/v), respectively. Proteins were visualized using ECL and exposure to Hyper Film ECL (Amersham Biosciences). To detect human Given the similarity of FHR-5 with fH and its association with clusterin in lipoprotein complexes, membranes were stripped by washing in complement deposits in vivo, we investigated whether recombi- 62 mM Tris, 2% SDS, 50 mM 2-ME at 42°C for 20 min, washed in PBS, nant FHR-5 (rFHR-5) exhibited functions associated with comple- and reprobed with mouse anti-human clusterin (K2.2G7) mAb (Ref.
Load more

Recommended publications
  • Regulation of the Complement System by Pentraxins
    REVIEW published: 02 August 2019 doi: 10.3389/fimmu.2019.01750 Regulation of the Complement System by Pentraxins Karita Haapasalo 1 and Seppo Meri 1,2,3* 1 Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland, 2 HUSLAB, Helsinki University Hospital, Helsinki, Finland, 3 Department of Biomedical Sciences, Humanitas University, Milan, Italy The functions of pentraxins, like C-reactive protein (CRP), serum amyloid protein P (SAP) and pentraxin-3 (PTX3), are to coordinate spatially and temporally targeted clearance of injured tissue components, to protect against infections and to regulate related inflammation together with the complement system. For this, pentraxins have a dual relationship with the complement system. Initially, after a focused binding to their targets, e.g., exposed phospholipids or cholesterol in the injured tissue area, or microbial components, the pentraxins activate complement by binding its first component C1q. However, the emerging inflammation needs to be limited to the target area. Therefore, pentraxins inhibit complement at the C3b stage to prevent excessive damage. The complement inhibitory functions of pentraxins are based on their ability to interact with complement inhibitors C4bp or factor H (FH). C4bp binds to SAP, while FH binds to Edited by: both CRP and PTX3. FH promotes opsonophagocytosis through inactivation of C3b to Barbara Bottazzi, Milan University, Italy iC3b, and inhibits AP activity thus preventing formation of the C5a anaphylatoxin and the Reviewed by: complement membrane attack complex (MAC). Monitoring CRP levels gives important Livija Deban, clinical information about the extent of tissue damage and severity of infections. CRP is a Prokarium, United Kingdom valuable marker for distinguishing bacterial infections from viral infections.
    [Show full text]
  • Nephrology Clinical Laboratory Research Compendium
    Nephrology Clinical Laboratory Research Compendium The Nephrology Clinical Laboratory at Cincinnati Children’s Hospital Medical Center has expanded its clinical testing menu to now offer testing on a research basis. The CAP and CLIA certified laboratory operates under Good Clinical Laboratory Practice principles to ensure testing can be used to support findings of clinical trials. CONTACT US Our state of the art laboratory offers a broad testing menu to support research and pharmaceutical projects. We have the capability to perform traditional For more information on research or ELISA’S, multiplexing using the MSD Meso discovery, luminex magnetic bead clinical testing, please contact us at: assays, nephelometry and clinical chemistry. Phone: 513-636-4530 [email protected] The Nephrology Clinical Laboratory Research Compendium offers clinical chemistry, therapeutic drug monitoring, immunology, complement quantitation, www.cincinnatichildrens.org function and activation, specialty proteins and testing for various forms of thrombotic microangiopathies. COMPLEMENT SPECIALTY TESTING Autoantibody Testing Complement Components • Factor H Autoantibody (Quantitative) • C3 Nephritic Factor • C1 inhibitor (quantitative) • Factor B Autoantibody • C1q • C2 Functional Testing • C3 • CH50 • C4 • Alternative Pathway Functional Assay • C5 • MBL Pathway Functional Assay • C6 • C1 inhibitor Functional Assay • C7 • C8 Complement Activation Fragments • C9 • Complement Bb • Factor B • Complement Ba • Factor H • C3a • Factor I • C3c • Properdin • C3d
    [Show full text]
  • O) 2 Platelets Mediated by Properdin and C3(H Complement Activation on Stimulated Identification of a Novel Mode Of
    Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2 O) This information is current as of October 1, 2021. Gurpanna Saggu, Claudio Cortes, Heather N. Emch, Galia Ramirez, Randall G. Worth and Viviana P. Ferreira J Immunol 2013; 190:6457-6467; Prepublished online 15 May 2013; doi: 10.4049/jimmunol.1300610 Downloaded from http://www.jimmunol.org/content/190/12/6457 Supplementary http://www.jimmunol.org/content/suppl/2013/05/17/jimmunol.130061 Material 0.DC1 http://www.jimmunol.org/ References This article cites 72 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/190/12/6457.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • 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 Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2O) Gurpanna Saggu,*,1 Claudio Cortes,*,†,1 Heather N.
    [Show full text]
  • Proteomic Alterations of HDL in Youth with Type 1 Diabetes and Their Associations with Glycemic Control: a Case-Control Study Evgenia Gourgari Georgetown University
    University of Kentucky UKnowledge Saha Cardiovascular Research Center Faculty Cardiovascular Research Publications 3-28-2019 Proteomic Alterations of HDL in Youth with Type 1 Diabetes and their Associations with Glycemic Control: A Case-Control Study Evgenia Gourgari Georgetown University Junfeng Ma Georgetown University Martin P. Playford National Heart, Lung and Blood Institute Nehal N. Mehta National Heart, Lung and Blood Institute Radoslav Goldman Georgetown University See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/cvrc_facpub Part of the Cardiology Commons, and the Circulatory and Respiratory Physiology Commons Repository Citation Gourgari, Evgenia; Ma, Junfeng; Playford, Martin P.; Mehta, Nehal N.; Goldman, Radoslav; Remaley, Alan T.; and Gordon, Scott M., "Proteomic Alterations of HDL in Youth with Type 1 Diabetes and their Associations with Glycemic Control: A Case-Control Study" (2019). Saha Cardiovascular Research Center Faculty Publications. 40. https://uknowledge.uky.edu/cvrc_facpub/40 This Article is brought to you for free and open access by the Cardiovascular Research at UKnowledge. It has been accepted for inclusion in Saha Cardiovascular Research Center Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Authors Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, and Scott M. Gordon Proteomic Alterations of HDL in Youth with Type 1 Diabetes and their Associations with Glycemic Control: A Case-Control Study Notes/Citation Information Published in Cardiovascular Diabetology, v.
    [Show full text]
  • Hemolytic Uremic Syndrome: a Factor H Mutation (E1172stop) Causes Defective Complement Control at the Surface of Endothelial Cells
    Hemolytic Uremic Syndrome: A Factor H Mutation (E1172Stop) Causes Defective Complement Control at the Surface of Endothelial Cells Stefan Heinen,* Miha´ly Jo´zsi,* Andrea Hartmann,* Marina Noris,† Giuseppe Remuzzi,† Christine Skerka,* and Peter F. Zipfel*‡ *Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, and ‡Faculty of Biology, Friedrich Schiller University, Jena, Germany; and †Mario Negri Institute for Pharmacological Research Villa Camozzi, Ranica, Bergamo, Italy Defective complement regulation results in hemolytic uremic syndrome (HUS), a disease that is characterized by microangi- opathy, thrombocytopenia, and acute renal failure and that causes endothelial cell damage. For characterization of how defective complement regulation relates to the pathophysiology, the role of the complement regulator factor H and also of a mutant factor H protein was studied on the surface of human umbilical vein endothelial cells. The mutant 145-kD factor H protein was purified to homogeneity, from plasma of a patient with HUS, who is heterozygous for a factor H gene mutation G3587T, which introduces a stop codon at position 1172. Functional analyses show that the lack of the most C-terminal domain short consensus repeats 20 severely affected recognition functions (i.e., binding to heparin, C3b, C3d, and the surface of endothelial cells). Wild-type factor H as well as the mutant protein formed dimers in solution as shown by cross-linking studies and mass spectroscopy. When assayed in fluid phase, the complement regulatory activity of the mutant protein was normal and comparable to wild-type factor H. However, on the surface of endothelial cells, the mutant factor H protein showed severely reduced regulatory activities and lacked protective functions.
    [Show full text]
  • Activation at Cell Surfaces Factor H in Regulating Complement Critical
    Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces This information is current as Viviana P. Ferreira, Andrew P. Herbert, Henry G. Hocking, of September 25, 2021. Paul N. Barlow and Michael K. Pangburn J Immunol 2006; 177:6308-6316; ; doi: 10.4049/jimmunol.177.9.6308 http://www.jimmunol.org/content/177/9/6308 Downloaded from References This article cites 69 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/177/9/6308.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 25, 2021 *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces1 Viviana P. Ferreira,* Andrew P. Herbert,† Henry G. Hocking,† Paul N. Barlow,† and Michael K.
    [Show full text]
  • Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis
    Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis This information is current as Damodar Gullipalli, Fengkui Zhang, Sayaka Sato, of September 29, 2021. Yoshiyasu Ueda, Yuko Kimura, Madhu Golla, Takashi Miwa, Jianxiang Wang and Wen-Chao Song J Immunol 2018; 201:1021-1029; Prepublished online 13 June 2018; doi: 10.4049/jimmunol.1800384 Downloaded from http://www.jimmunol.org/content/201/3/1021 References This article cites 37 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/201/3/1021.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis Damodar Gullipalli,* Fengkui Zhang,† Sayaka Sato,* Yoshiyasu Ueda,* Yuko Kimura,* Madhu Golla,* Takashi Miwa,* Jianxiang Wang,† and Wen-Chao Song* Paroxysmal nocturnal hemoglobinuria (PNH) is a serious blood disorder characterized by dysregulated complement activation on blood cells.
    [Show full text]
  • Factor H and Atypical Hemolytic Uremic Syndrome: Mutations in the C-Terminus Cause Structural Changes and Defective Recognition Functions
    Factor H and Atypical Hemolytic Uremic Syndrome: Mutations in the C-Terminus Cause Structural Changes and Defective Recognition Functions Miha´ly Jo´zsi,* Stefan Heinen,* Andrea Hartmann,* Clemens W. Ostrowicz,* Steffi Ha¨lbich,* Heiko Richter,* Anja Kunert,* Christoph Licht,† Rebecca E. Saunders,‡ Stephen J. Perkins,‡ Peter F. Zipfel,*§ and Christine Skerka* *Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany; †Children’s Hospital of the University of Cologne, Pediatric Nephrology, Cologne, Germany; ‡Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, London, United Kingdom; and §Frierich Schiller University, Jena, Germany Atypical hemolytic uremic syndrome is a disease that is characterized by microangiopathic hemolytic anemia, thrombocyto- penia, and acute renal failure. Mutations in the complement regulator factor H are associated with the inherited form of the disease, and >60% of the mutations are located within the C terminus of factor H. The C-terminus of factor H, represented by short consensus repeat 19 (SCR19) and SCR20, harbors multiple functions; consequently, this study aimed to examine the functional effects of clinically reported mutations in these SCR. Mutant factor H proteins (W1157R, W1183L, V1197A, R1210C, R1215G, and P1226S) were recombinantly expressed and functionally characterized. All six mutant proteins showed severely reduced heparin, C3b, C3d, and endothelial cell binding. By peptide spot analyses, four linear regions that are involved in heparin, C3b, and C3d binding were localized in SCR19 and SCR20. A three-dimensional homology model of the two domains suggests that these four regions form a common binding site across both domains.
    [Show full text]
  • C1-Esterase Inhibitor
    & Throm gy b o o l e o t m Journal of Hematology & a b o m Karnaukhova, J Hematol Thromb Dis 2013, 1:3 l e i c H D f DOI: 10.4172/2329-8790.1000113 o i s l e a Thromboembolic Diseases ISSN: 2329-8790 a n s r e u s o J Review Article Open Access C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications Elena Karnaukhova* Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, 20892 USA Abstract Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibi- tor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in hereditary angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma. Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic ap- plication of C1-INH.
    [Show full text]
  • Supplementary Figure 1. Estimation of the Percentage of Volume of Each Population of Extracellular Vesicles by Dynamic Light Scattering
    Supplementary Figure 1. Estimation of the percentage of volume of each population of extracellular vesicles by Dynamic light scattering. Each line represents an independent run. Supplementary Table 1. Differential protein expressionidentified by SWATH MS in neonatalexosomescompared to adultsexosomes (p < 0.05; FCh≠1). Ig: Immunoglobulin. Fold Uniprot Name Gene Name Protein Name p value Change P02786 TFR1 Transferrin receptor protein 1 0.00104 15.32 Q99808 S29A1 Equilibrative nucleide transporter 1 0.01424 14.01 Solute carrier family 2, facilitated glucose P11166 GTR1 0.00106 10.15 transporter member 1 P69892 HBG2 Hemoglobin subunit γ-2 0 9.43 P02792 FRIL Ferritin light chain 0.00438 9.22 Q16819 MEP1A Meprin A subunitα 0.01481 7.13 P02776 PLF4 Platelet factor 4 0.00809 7.01 Q02094 RHAG Ammonium transporter Rh type A 0.00772 6.71 P27918 PROP Properdin 0 6.26 P16671 CD36 Platelet glycoprotein 4 0.00001 5.99 G-protein coupled receptor family C group 5 Q9NQ84 GPC5C 0.00467 5.87 member C P08195 4F2 4F2 cell-surface antigen heavy chain 0.00224 5.77 Q658P3 STEA3 Metalloreductase STEAP3 0.00262 5.34 Q6UX06 OLFM4 Olfactomedin-4 0.00008 5.08 P02787 TRFE Serotransferrin 0.00101 5.05 P08514 ITA2B Integrin αIIb 0 4.88 P02730 B3AT Band 3 anion transport protein 0.00334 4.71 P11142 H7C Heat shock cognate 71 kDa protein 0.00239 4.7 2 of 6 Q15758 AAAT Neutral amino acid transporter B(0) 0.00829 4.56 P05164 PERM Myeloperoxidase 0.00003 4.46 P0DMV9 HS71B Heat shock 70 kDa protein 1B 0.0012 4.36 Erythrocyte band 7 integral P27105 STOM 0.00326 4.18 membrane
    [Show full text]
  • Monoclonal Antibodies: Anti-Human Factor H#2
    TDA254000EN00.qxp_Layout 1 11/16/16 10:12 AM Page 1 Technical Data Sheet Monoclonal Antibodies: Anti-Human Factor H#2 For Research Use Only. Not for use in diagnostic procedures Background Factor H is a fluid phase complement regulatory protein consisting of a single peptide chain of 20 short consensus repeat segments or CCP’s with a molecular weight of approximately 155 KD. 1 Factor H regulates the alternative pathway of the complement system by modifying activity of the “feedback loop.” It does this in three ways. First, it is a co-factor for the serine protease Factor I, which cleaves C3b to iC3b. iC3b has no hemolytic or amplification function, but may be bound by complement receptors. Second, Factor H prevents the formation of and accelerates the disassociation of the alternative pathway C3 convertase, C3bBb from cell surfaces. Finally, Factor H binds to polyanions on host cell surfaces and tissue matrices, such as basement membranes, blocking deposition of C3b. This later activity is leveraged by many pathogens as a mode of complement evasion. 2 Recent studies have linked Factor H to hemolytic uremia syndrome (HUS), 3 age-related macular degeneration (AMD), 4 and membrano-proliferative glomerulonephritis. Factor H may also be elevated in certain cancers, including bladder cancer, potentially as a protective measure used by tumor cells to evade complement attack. 4 Characterization All of Quidel’s monoclonal antibodies to complement antigens were prepared using intact complement proteins and are purified from mouse ascites fluid via protein A affinity chromatography. The prepared monoclonal antibodies are buffer exchanged in Borate Buffered Saline containing 0.02% NaN 3.
    [Show full text]
  • The Alternative Complement Pathway Is Activated in Protoporphyria Patients During Sun Exposure
    medRxiv preprint doi: https://doi.org/10.1101/2020.10.12.20210344; this version posted October 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. The alternative complement pathway is activated in protoporphyria patients during sun exposure. Francesca Granata1*; Lorena Duca1; Valentina Brancaleoni1; Silvia Fustinoni2-3; Giacomo De Luca1; Irene Motta1-4; Giovanna Graziadei1; Elena Di Pierro1 1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, U.O.C. Medicina Generale, Milano, Italy 2 EPIGET - Epidemiology, Epigenetics, and Toxicology Lab, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy 3 Environmental and Industrial Toxicology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy 4 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy *Corresponding author: Francesca Granata, MSc Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Via F. Sforza 3520122 Milan, Italy Email: [email protected] Tel: +39 0255033363 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.10.12.20210344; this version posted October 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. ABSTRACT The homeostasis of tissues in chronic disease is an important function of the alternative pathway (AP) of the complement system (CS).
    [Show full text]