Disease relevance of C9

• Both subunits of clusterin interact with C9 and are similarly potent in inhibiting C5b-9-mediated hemolysis and Zn+(+)-induced C9 polymerization [1].
• There was a highly significant reduction in cerebrospinal fluid C9 concentration in patients with multiple sclerosis (0.26 +/- 0.02 microgram/ml) compared with controls (1.52 +/- 0.20 micrograms/ml; p less than 0.0005) [2].
• The role of C9 in complement-mediated killing of Neisseria [3].
• Activation of the terminal complement cascade involving C5 to C9 proteins has a beneficial role for oligodendrocytes (OLG) in experimental allergic encephalomyelitis, an animal model of multiple sclerosis, by protecting them from apoptotic cell death [4].
• Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis [5].

Psychiatry related information on C9

• Here, we present evidence from ELISA assays that CD59 protein levels are significantly decreased in the frontal cortex and hippocampus of Alzheimer's disease (AD) compared with nondemented elderly (ND) patients, whereas complement component 9, a final component to form MAC, is significantly increased [6].
• METHODS: Substantia nigra specimens from young normal subjects (n = 11-13), aged normal subjects (n = 24-28), and subjects with PD (n = 19-20), Alzheimer's disease (AD; n = 12-13), and dementia with Lewy bodies (DLB; n = 9) were stained for iC3b and C9, representing early- and late-stage complement activation, respectively [7].

High impact information on C9

• The ninth component of complement (C9) and the pore-forming protein (PFP or perforin) from cytotoxic T lymphocytes polymerize to tubular lesions having an internal diameter of 100 A and 160 A, respectively, when bound to lipid bilayers [8].
• Polymerized C9, assembled by slow spontaneous or rapid Zn2+-induced polymerization, and polyperforin, which is assembled only in the presence of Ca2+, constitute large aqueous pores that are stable, nonselective for solutes, and insensitive to changes of membrane potential [8].
• Although its mechanism of action is not well understood, CD59 is thought to prevent assembly of the MAC by binding to the C8 and/or C9 proteins of the nascent complex [9].
• Polyclonal antibodies raised against purified human C5b-6, C7, C8, or C9 react with other components of the MAC and with mouse lymphocyte PFP [10].
• Presensitization of GC with increasing concentrations of blocking IgG or F(ab')2 before incubation with bactericidal antibody and absorbed pooled normal human serum increased consumption and deposition of the third component of human complement (C3) and the ninth component of human complement (C9) but inhibited killing in dose-related fashion [11].

Chemical compound and disease context of C9

• In this study, we investigated the production of complement components C2, C4, and C9 by human monocytes/macrophages and by the pathologic cells of acute monocytic leukemia which represent a source of immature monocytic precursors [12].
• She was admitted with hematuria and proteinuria, and the C9 deficiency was diagnosed based on the low hemolytic activity of 50 % of the hemolytic unit of the complements (CH50) and the normal C3 level in the plasma [13].

Biological context of C9

• The human genes for complement components 6 (C6) and 9 (C9) are closely linked on chromosome 5 [14].
• The amino acid sequence predicted from the open reading frame of this cDNA concurs with the amino acid sequence at the amino-terminal end of three proteolytic fragments of purified C9 protein [15].
• A partial nucleotide sequence of human complement component C9 cDNA representing 94% of the coding region of the mature protein is presented [15].
• These results indicate that a CD59 binding site is located between residues 320 and 411 of the C9 polypeptide and suggest that the affinity of this site is principally determined by residues 359-411 [16].
• As a screening step for mutations, exons 2 to 11 of the C9 gene were analyzed using exon-specific PCR/single-strand conformation polymorphism analysis, which demonstrated aberrantly migrating DNA bands in exon 4 in all the C9D subjects [17].

Anatomical context of C9

• Equine C9, in contrast to human C9, has extremely low hemolytic activity against most mammalian erythrocytes, although the amino acid sequences of both proteins show 77% identity [18].
• In an attempt to define the region of human C9 responsible for conferring its lytic activity, or conversely, the region of equine C9 responsible for its restriction, recombinant human and equine C9 and four chimeric human/equine C9 proteins were constructed and expressed in COS-7 cells [18].
• This was achieved by using a novel application of the polymerase chain reaction to amplify specifically the human C9 gene on a background of rodent DNA in somatic cell hybrids [19].
• The domain of the unfolded protein interacting with the cell membrane has so far not been identified since, unlike many integral membrane proteins, the C9 sequence does not contain a continuous stretch of hydrophobic amino acids [20].
• Terminal component of complement (C9) in cerebrospinal fluid of patients with multiple sclerosis [2].

Associations of C9 with chemical compounds

• DNA polymorphisms and linkage relationship of the human complement component C6, C7, and C9 genes [21].
• The amino-terminal half of C9 is rich in cysteine residues and contains a region with a high level of homology to the LDL receptor cysteine-rich domains [15].
• These results may indicate the presence of surface-binding domains in the NH2-terminal half and channel-forming domains in the COOH-terminal portion of native, monomeric C9 [22].
• In case 6, the second mutation for C9D of the C9 gene was identified to be the substitution of Cys to Tyr at amino acid residue 507 (C507Y), while the genetic defect(s) in the other allele in case 7 remains unknown [17].
• Perforin, unlike C9, is not dependent on a protein receptor molecule but binds to the target cell membrane via phosphorylcholine in a Ca2(+)-dependent manner [23].

Regulatory relationships of C9

• Affinity-purified antibody against C9 residues 320-411 inhibited CD59 binding to C9 by > 50% and completely inhibited its binding to the isolated C9b domain [16].

Other interactions of C9

• Polymorphisms have been described at the DNA level for the C7 and C9 genes [21].
• When thrombin-treated C9 was analyzed, clusterin was found to recognize the C9b fragment containing the hydrophobic membrane interaction segment [1].
• Identity of a peptide domain of human C9 that is bound by the cell-surface complement inhibitor, CD59 [16].
• This exon is separated by 1.7 kb from the second exon containing the remaining (4 bp) 5' untranslated region, the leader peptide and the N-terminal region of P1 up to--but not including--the C9 homologous region [24].
• We deduce that substantial rearrangement of the exon-intron structure of the C9 gene must have occurred before the exchange of cysteine-rich domains, possibly linked to the process of exon duplication which was required to generate the repeats in the LDL receptor [25].

Analytical, diagnostic and therapeutic context of C9

• Monoclonal antibody epitopes have been mapped by comparing overlapping fragments of C9 molecule to which the antibodies bind on Western blots [15].
• An immunoradiometric assay was used to measure the concentration of the terminal component of complement (C9) in cerebrospinal fluid (CSF) and plasma from 35 patients with multiple sclerosis and 55 controls with other neurological diseases [2].
• Using the procedure that was developed for the isolation of C9RP from large granular lymphocytes--i.e., affinity chromatography employing anti-human C9 linked to Sepharose, a cytolytic protein has now been isolated from OKT3-activated human peripheral blood mononuclear cells [26].
• The other half of the C9 associates with a second population of SUV without causing a change in Stokes' radius of these vesicles, and no proteinaceous structures are detectable on the vesicle surface by electron microscopy [27].
• Such antibodies react in several immunoassays with human and monkey C9 but not with C9 from lower animals, and no inhibition of lysis mediated by C9 molecules from these animals is observed [28].

References