8eok

From Proteopedia

(Difference between revisions)

Current revision

Structure of the C3bB proconvertase in complex with lufaxin and factor Xa

Structural highlights

8eok is a 6 chain structure with sequence from Homo sapiens and Lutzomyia longipalpis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.53Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LUFX_LUTLO Sand fly salivary protein with antithrombotic, and anti-complement (alternative pathway) activities (PubMed:22796577, PubMed:28912782). Is a slow, tight, non-competitive, and reversible inhibitor of factor Xa (FXa, F10) (PubMed:22796577). Is specific for FXa (Kd=3.86 nM) and does not interact with non-activated FX, or all other enzymes tested (PubMed:22796577). In addition, it blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time (PubMed:22796577). It also prevents protease-activated receptor 2 (F2RL1, PAR2) activation by FXa (PubMed:22796577). In vivo, it abrogates edema formation triggered by injection of FXa in the paw of mice (PubMed:22796577). Moreover, it prevents FeCl3-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo (PubMed:22796577). It also inhibits the early steps of the alternative pathway of complement by direct binding to the proconvertase C3b-B complex, by inhibiting activation of factor B and consequently the formation of the C3 convertase (PubMed:28912782).^[1] ^[2]

Publication Abstract from PubMed

Inhibitors of complement and coagulation are present in the saliva of a variety of blood-feeding arthropods that transmit parasitic and viral pathogens. Here, we describe the structure and mechanism of action of the sand fly salivary protein lufaxin, which inhibits the formation of the central alternative C3 convertase (C3bBb) and inhibits coagulation factor Xa (fXa). Surface plasmon resonance experiments show that lufaxin stabilizes the binding of serine protease factor B (FB) to C3b but does not detectably bind either C3b or FB alone. The crystal structure of the inhibitor reveals a novel all beta-sheet fold containing 2 domains. A structure of the lufaxin-C3bB complex obtained via cryo-electron microscopy (EM) shows that lufaxin binds via its N-terminal domain at an interface containing elements of both C3b and FB. By occupying this spot, the inhibitor locks FB into a closed conformation in which proteolytic activation of FB by FD cannot occur. C3bB-bound lufaxin binds fXa at a separate site in its C-terminal domain. In the cryo-EM structure of a C3bB-lufaxin-fXa complex, the inhibitor binds to both targets simultaneously, and lufaxin inhibits fXa through substrate-like binding of a C-terminal peptide at the active site as well as other interactions in this region. Lufaxin inhibits complement activation in ex vivo models of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) as well as thrombin generation in plasma, providing a rationale for the development of a bispecific inhibitor to treat complement-related diseases in which thrombosis is a prominent manifestation.

A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism.,Andersen JF, Lei H, Strayer EC, Kanai T, Pham V, Pan XZ, Alvarenga PH, Gerber GF, Asojo OA, Francischetti IMB, Brodsky RA, Valenzuela JG, Ribeiro JMC Blood. 2023 Jun 22;141(25):3109-3121. doi: 10.1182/blood.2022019359. PMID:36947859^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Collin N, Assumpção TC, Mizurini DM, Gilmore DC, Dutra-Oliveira A, Kotsyfakis M, Sá-Nunes A, Teixeira C, Ribeiro JM, Monteiro RQ, Valenzuela JG, Francischetti IM. Lufaxin, a novel factor Xa inhibitor from the salivary gland of the sand fly Lutzomyia longipalpis blocks protease-activated receptor 2 activation and inhibits inflammation and thrombosis in vivo. Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2185-98. PMID:22796577 doi:10.1161/ATVBAHA.112.253906
↑ Mendes-Sousa AF, do Vale VF, Silva NCS, Guimaraes-Costa AB, Pereira MH, Sant'Anna MRV, Oliveira F, Kamhawi S, Ribeiro JMC, Andersen JF, Valenzuela JG, Araujo RN. The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B. Front Immunol. 2017 Aug 31;8:1065. PMID:28912782 doi:10.3389/fimmu.2017.01065
↑ Andersen JF, Lei H, Strayer EC, Kanai T, Pham V, Pan XZ, Alvarenga PH, Gerber GF, Asojo OA, Francischetti IMB, Brodsky RA, Valenzuela JG, Ribeiro JMC. A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism. Blood. 2023 Jun 22;141(25):3109-3121. PMID:36947859 doi:10.1182/blood.2022019359

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8eok"

Categories: Homo sapiens | Large Structures | Lutzomyia longipalpis | Andersen JF | Lei H

@@ Line 8: / Line 8: @@
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8eok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8eok OCA], [https://pdbe.org/8eok PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8eok RCSB], [https://www.ebi.ac.uk/pdbsum/8eok PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8eok ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:[https://omim.org/entry/613779 613779]. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis.<ref>PMID:19913840</ref> <ref>PMID:9596584</ref> <ref>PMID:11387479</ref> <ref>PMID:15713468</ref> <ref>PMID:7961791</ref> [:]  Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:[https://omim.org/entry/611378 611378]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:19913840</ref> <ref>PMID:17634448</ref>   Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:[https://omim.org/entry/612925 612925]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19913840</ref> <ref>PMID:18796626</ref> <ref>PMID:20513133</ref>   Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.<ref>PMID:19913840</ref>
 == Function ==
-[https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>   Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>   Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>
+[https://www.uniprot.org/uniprot/LUFX_LUTLO LUFX_LUTLO] Sand fly salivary protein with antithrombotic, and anti-complement (alternative pathway) activities (PubMed:22796577, PubMed:28912782). Is a slow, tight, non-competitive, and reversible inhibitor of factor Xa (FXa, F10) (PubMed:22796577). Is specific for FXa (Kd=3.86 nM) and does not interact with non-activated FX, or all other enzymes tested (PubMed:22796577). In addition, it blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time (PubMed:22796577). It also prevents protease-activated receptor 2 (F2RL1, PAR2) activation by FXa (PubMed:22796577). In vivo, it abrogates edema formation triggered by injection of FXa in the paw of mice (PubMed:22796577). Moreover, it prevents FeCl3-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo (PubMed:22796577). It also inhibits the early steps of the alternative pathway of complement by direct binding to the proconvertase C3b-B complex, by inhibiting activation of factor B and consequently the formation of the C3 convertase (PubMed:28912782).<ref>PMID:22796577</ref> <ref>PMID:28912782</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

8eok

From Proteopedia

Current revision

Structure of the C3bB proconvertase in complex with lufaxin and factor Xa

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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