Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.
Mol Immunol 2008 Oct
PMID:Biological activities of C1 inhibitor. 1867 18

Poly(ethylene glycol) (PEG) is receiving increasing attention as an intravenous therapeutic agent per se in a variety of experimental therapeutics and veterinary settings, such as spinal cord injury and traumatic axonal brain injury. PEG is often perceived to be immunologically safe, but here we demonstrate that near-monodisperse endotoxin-free PEGs, at concentrations relevant to above-mentioned settings, can generate complement activation products in human serum on a time scale of minutes (reflected in significant rises in serum levels of C4d, Bb, C3a-desArg and SC5b-9). With the aid of sera depleted from either C2 or C1q, and devoid of anti-PEG antibodies, we further demonstrate that, depending on PEG concentration and M(wt), generation of complement activation products occur either exclusively through the lectin pathway activation or through both the lectin pathway and increased fluid phase turnover of the alternative pathway. Inhibition of PEG-mediated C4d elevation in C1q-depleted serum by the broad serine protease inhibitor Futhan and anti-MASP-2 antibodies as well as competitive studies with d-mannose and N-acetylglucosamine indicated a likely role for ficolins/MASP-2 in PEG-mediated triggering of the lectin pathway and independent of calcium. PEG-mediated amplification of the alternative pathway is a complex process related to protein partitioning and exclusion effect, but factor H depletion/exclusion seems to play a minor role. Our results are relevant to the proposed potential therapeutic applications of intravenous PEG and warn about possible acute PEG infusion-related reactions in sensitive individuals and animals. PEG-mediated generation of complement activation products further provides a plausible explanation to the previously reported unexplained anaphylaxis or the referred cardiovascular collapse in sensitive animals that have received medicines containing high levels of PEG as solubilizer/carrier.
Mol Immunol 2008 Dec
PMID:Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. 1884 76

Ficolins and one collectin, mannan-binding lectin (MBL), are the only factors known to activate the lectin pathway (LP) of complement. There is considerable circumstantial evidence that MBL insufficiency can increase susceptibility to various infections and influence the course of several non-infectious diseases complicated by infections. Much less information is available concerning l-ficolin. We report the results of a prospective study to investigate any association between either MBL deficiency or l-ficolin deficiency with prematurity, low birthweight or perinatal infections in a large cohort of Polish neonates, representing an ethnically homogenous population (n=1832). Cord blood samples were analysed to determine mbl-2 gene variants, MBL concentrations and MBL-MASP-2 complex activities (MBL-dependent lectin pathway activity) as well as l-ficolin levels. Median concentrations of l-ficolin and MBL were 2500 and 1124 ng/ml, respectively, while median LP activity was 272 mU/ml. After genotyping, 60.6% of babies were mbl-2 A/A, 35.4% were A/O and 4% were O/O genotypes. We found relative l-ficolin deficiency to be associated with prematurity, low birthweight and infections. l-Ficolin concentration correlated with gestational age and with birthweight, independently of gestational age. Preterm deliveries (<38 weeks) occurred more frequently among neonates with low LP activity but not with those having low serum MBL levels. Similarly, no association of serum MBL deficiency with low birthweight was found, but there was a correlation between LP activity and birthweight. Genotypes conferring very low serum MBL concentrations were associated with perinatal infections, and high-MBL-conferring genotypes were associated with prematurity. Our findings suggest that l-ficolin participates in host defence during the perinatal period and constitute the first evidence that relative l-ficolin deficiency may contribute to the adverse consequences of prematurity. Some similar trends were found with facets of MBL deficiency, but the observed relationships were weaker and less consistent.
Mol Immunol 2009 Feb
PMID:Two factors of the lectin pathway of complement, l-ficolin and mannan-binding lectin, and their associations with prematurity, low birthweight and infections in a large cohort of Polish neonates. 1895 Aug 64

Complement activation is initiated by the pattern-recognition molecules complement component C1q, mannose-binding lectin (MBL) and ficolins (H-, L-, M-ficolin), which typically recognize antibody-antigen complexes or foreign polysaccharides. The associated proteases (C1r, C1s, MASP-1 and MASP-2) then activate the complement system. The serpin C1-inhibitor (C1-inh) blocks activity of all these complexes and has been successfully used in models of disease. Many structures of these components became available recently, including that of C1-inh, facilitating the structure-guided design of drugs targeting complement activation. Here, we propose an approach in which therapeutic proteins are made up of natural protein domains and C1-inh to allow targeting to the site of inflammation and more specific inhibition of complement activation. In particular, engineering a fast-acting C1-inh or fusing it to an 'aiming module' has been shown to be feasible and economical using a humanized yeast expression system. Complement-mediated inflammation has been linked to ischemia-reperfusion injury, organ graft rejection and even neurodegeneration, so targeting this process has direct clinical implications.
Trends Mol Med 2008 Dec
PMID:C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. 1897 95

The Tudor-SN protein (p100, SND1) has been implicated in a variety of cellular processes, such as transcription, processing of edited double-stranded RNA, and splicing regulation. Molecular details of these functions are not yet understood. Tudor domains have previously been shown to bind methylated ligands, such as methylated lysines and arginines. It has been suggested that the role of Tudor-SN in splicing may involve binding to such methylated ligands or to the methylated 5' cap of spliceosomal snRNAs. Here, we report the crystal structure of the extended Tudor domain of Tudor-SN from Drosophila melanogaster to a resolution of 2.1 A. NMR secondary chemical shifts, relaxation data, and residual dipolar couplings indicate that the solution and crystal structures are similar. Binding of various ligands was investigated by NMR. Binding sites and affinities were characterized by chemical shift perturbations. We show that the aromatic cage of the Tudor domain specifically binds a peptide containing symmetrically dimethylated arginines (sDMA) with micromolar affinity, while the same peptide comprising nonmethylated arginines does not show significant chemical shift perturbations. Tudor-SN preferentially recognizes sDMA over asymmetrically dimethylated arginine (aDMA). In contrast, two 5' cap analogues with different methylation patterns, as well as mono-, di-, and trimethyllysines, show no binding. Our data demonstrate that the Tudor domain of Tudor-SN specifically recognizes sDMA-containing ligands. The aromatic cage of Tudor-SN is very similar to the one in the Tudor domain of the survival of motor neuron protein, which also recognizes sDMA peptides, indicating a conserved binding motif for this methylation mark. Recognition of sDMA in the C-terminal tails of spliceosomal Sm proteins suggests how Tudor-SN may interact with small nuclear ribonucleoprotein particles during the regulation of splicing.
J Mol Biol 2009 Apr 10
PMID:Structure and ligand binding of the extended Tudor domain of D. melanogaster Tudor-SN. 1923 56

NSC 676914 has been identified as a selective nuclear factor-kappaB (NF-kappaB) inhibitor that does not inhibit cell proliferation. This compound was originally identified in a high-throughput cell-based assay for activator protein-1 (AP-1) inhibitors using synthetic compound libraries and the National Cancer Institute natural product repository. NSC 676914 shows activity against NF-kappaB in luciferase reporter assays at concentrations much less than the IC50 for AP-1. A serum response element reporter used as a specificity control and indicator of cell proliferation was relatively insensitive to the compound. Pretreatment with NSC 676914 is here shown to repress 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IkappaB-alpha phosphorylation and translocation of p65/50 to the nucleus but not the processing of p52 from p100, suggesting the inhibition of NF-kappaB regulator IKKbeta rather than IKKalpha. Inhibition of NF-kappaB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IkappaB-alpha phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 mumol/L. In contrast, kinases c-Jun-NH2-kinase and extracellular signal-regulated kinases 1 and 2, important for AP-1 activation, showed no significant repression by this compound. Furthermore, a Matrigel invasion assay with breast cancer cell lines and a transformation assay in mouse JB6 cells revealed that TPA-induced invasion and transformation responses were completely repressed by this compound. These results suggest that NSC 676914 could be a novel inhibitor having potential therapeutic activity to target NF-kappaB for cancer treatment or prevention.
Mol Cancer Ther 2009 Mar
PMID:A selective small-molecule nuclear factor-kappaB inhibitor from a high-throughput cell-based assay for "activator protein-1 hits". 1925 26

One collectin (mannan-binding lectin, MBL) and three ficolins (M-ficolin/ficolin-1, L-ficolin/ficolin-2 and H-ficolin/ficolin-3) share the capability to activate complement via the lectin pathway. This property depends on the ability of these lectins to form complexes with MBL-associated serine proteases (MASPs), particularly MASP-2. We report the results of an investigation of cord blood MASP-2 concentrations in a large, ethnically homogeneous cohort (n=1788) of neonates. The median value of MASP-2 in cord sera was determined to be 93 ng/ml (range <25-812). Serum MASP-2 concentrations correlated with gestational age and birthweight and were significantly lower in premature babies and other pre-term babies compared with term babies. Neonates with MASP-2 concentrations below 42 ng/ml were deemed to be MASP-2 deficient. That group had a shorter mean gestational age and a higher incidence of premature and low birthweight babies, but not of perinatal infections when compared with the others. Indeed, there was a trend towards higher MASP-2 concentrations amongst babies with infections. Among 362 samples tested for the D120G single nucleotide polymorphism (SNP) of the MASP2 gene, no homozygote for that mutation was found. Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity (MBL-MASP-2 complex activity). Moreover, no association of this SNP was apparent with prematurity, low birthweight or perinatal infections.
Mol Immunol 2009 May
PMID:Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations. 1930 21

Nfkb1 and Nfkb2 proteins p105 and p100 serve both as NF-kappaB precursors and inhibitors of NF-kappaB dimers. In a biochemical characterization of endogenous cytoplasmic and purified recombinant proteins, we found that p105 and p100 assemble into high-molecular-weight complexes that contribute to the regulation of all NF-kappaB isoforms. Unlike the classical inhibitors IkappaBalpha, -beta, and -epsilon, high-molecular-weight complexes of p105 and p100 proteins bind NF-kappaB subunits in two modes: through direct dimerization of Rel homology domain-containing NF-kappaB polypeptides and through interactions of the p105 and p100 ankyrin repeats with preformed NF-kappaB dimers, thereby mediating the bona fide IkappaB activities, IkappaBgamma and IkappaBdelta. Our biochemical evidence suggests an assembly pathway in which kinetic mechanisms control NF-kappaB dimer formation via processing and assembly of large complexes that contain IkappaB activities.
Mol Cell 2009 Jun 12
PMID:The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. 1952 38

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is unique among the members of the TRAF family, as it lacks the N-terminal RING/zinc-finger domain. Also the function of TRAF1 is not clearly established, with many papers reporting contradictory results. Here we show that TRAF1 interacts with BAFF receptor, a member of the TNF receptor family, and positively regulates activation of the alternative NF-kappaB pathway. Ectopic expression of TRAF1 causes degradation of TRAF3, stabilization of NIK, and processing of p100 to produce the mature form p52. In addition, we show that knocking-down expression of TRAF1 in the Hodgkin's disease derived cell line L1236, interfere with p100 processing and with p52 mediate gene transcription. Collectively these results support a role for TRAF1 as a positive regulator of the NF-kappaB alternative pathway.
Mol Immunol 2009 Oct
PMID:TNF receptor-associated factor 1 is a positive regulator of the NF-kappaB alternative pathway. 1969 91

Mycobacterium tuberculosis is the leading cause of infectious disease in humans in the world. It evades the host immune system by being phagocytosed by macrophages and residing intracellularly. Complement-dependent opsonisation of extracellular mycobacteria may assist them to enter macrophages. This work examines in detail the mechanisms of complement activation by whole mycobacteria using Mycobacterium bovis BCG as a model organism. M. bovis BCG directly activates the classical, lectin and alternative pathways, resulting in fixation of C3b onto macromolecules of the mycobacterial surface. Investigation into the classical pathway has shown direct binding of human C1q to whole mycobacteria in the absence of antibodies. Most human sera contain IgG and IgM-anti-(M. bovis BCG), and pre-incubation with human immunoglobulin enhances C1q binding to the bacteria. Therefore classical pathway activation is both antibody-independent and dependent. The bacteria also activate the alternative pathway in an antibody-independent manner, but Factor H also binds, suggesting some regulation of amplification by this pathway. For the lectin pathway we have demonstrated direct binding of both MBL and L-ficolin from human serum to whole mycobacteria and subsequent MASP2 activation. H-ficolin binding was not observed. No M. bovis BCG cell surface or secreted protease appears likely to influence complement activation. Together, these data provide a more detailed analysis of the mechanisms by which M. bovis BCG interacts with the complement system.
Mol Immunol 2009 Oct
PMID:Multiple routes of complement activation by Mycobacterium bovis BCG. 1969 93


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