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Membrane pore formation by human complement: functional importance of the transmembrane ?-hairpin (TMH) segments of C8? and C9.

ABSTRACT: Human C8 and C9 have a key role in forming the pore-like "membrane attack complex" (MAC) of complement on bacterial cells. A possible mechanism for membrane insertion of these proteins was suggested when studies revealed a structural similarity between the MACPF domains of the C8? and C8? subunits and the pore-forming bacterial cholesterol-dependent cytolysins (CDCs). This similarity includes a pair of ?-helical bundles that in the CDCs refold during pore formation to produce two transmembrane ?-hairpins (TMH1 and TMH2). C9 is the major pore-forming component of the MAC and is also likely to contain two TMH segments because of its homology to C8? and C8?. To determine their potential for membrane insertion, the TMH sequences in C8? and those predicted to be in C9 were substituted for the TMH sequences in perfringolysin O (PFO), a well-characterized CDC. Only chimeric proteins containing TMH2 from C8? (PFO/?T2) or C9 (PFO/C9T2) could be expressed in soluble, active form. The PFO/?T2 and PFO/C9T2 chimeras retained significant hemolytic activity, formed pore-like structures on membranes, and could combine with PFO to form hemolytically active mixed complexes that were functionally similar to PFO alone. These results provide experimental evidence in support of the hypothesis that TMH segments in C8? and those predicted to be in C9 have a direct role in MAC membrane penetration and pore formation.

SUBMITTER: Weiland MH

PROVIDER: S-EPMC3856643 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Membrane pore formation by human complement: functional importance of the transmembrane β-hairpin (TMH) segments of C8α and C9.

Weiland Mitch H MH Qian Yu Y Sodetz James M JM

Molecular immunology 20131112 2

Human C8 and C9 have a key role in forming the pore-like "membrane attack complex" (MAC) of complement on bacterial cells. A possible mechanism for membrane insertion of these proteins was suggested when studies revealed a structural similarity between the MACPF domains of the C8α and C8β subunits and the pore-forming bacterial cholesterol-dependent cytolysins (CDCs). This similarity includes a pair of α-helical bundles that in the CDCs refold during pore formation to produce two transmembrane β ...[more]

PMID: 24239861

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Project description:The complement system is a part of the natural immune regulation mechanism against invading pathogens. Complement activation from three different pathways (classical, lectin, and alternative) leads to the formation of C5-convertase, an enzyme for cleavage of C5 into C5a and C5b, followed by C6, C7, C8, and C9 in membrane attack complex. The C9 is the last complement component of the terminal lytic pathway, which plays an important role in lysis of the target cells depending on its self-polymerization to form transmembrane channels. To address the association of C9 with traits related to disease resistance, the complete porcine C9 cDNA was comparatively sequenced to detect single nucleotide polymorphisms (SNPs) in pigs of the breeds Hampshire (HS), Duroc (DU), Berlin miniature pig (BMP), German Landrace (LR), Pietrain (PIE), and Muong Khuong (Vietnamese potbelly pig). Genotyping was performed in 417 F2 animals of a resource population (DUMI: DU×BMP) that were vaccinated with Mycoplasma hyopneumoniae, Aujeszky diseases virus and porcine respiratory and reproductive syndrome virus at 6, 14 and 16 weeks of age, respectively. Two SNPs were detected within the third exon. One of them has an amino acid substitution. The European porcine breeds (LR and PIE) show higher allele frequency of these SNPs than Vietnamese porcine breed (MK). Association of the substitution SNP with hemolytic complement activity indicated statistically significant differences between genotypes in the classical pathway but not in the alternative pathway. The interactions between eight time points of measurement of complement activity before and after vaccinations and genotypes were significantly different. The difference in hemolytic complement activity in the both pathways depends on genotype, kind of vaccine, age and the interaction to the other complement components. These results promote the porcine C9 (pC9) as a candidate gene to improve general animal health in the future.

Dataset Information

Membrane pore formation by human complement: functional importance of the transmembrane ?-hairpin (TMH) segments of C8? and C9.

Publications

Membrane pore formation by human complement: functional importance of the transmembrane β-hairpin (TMH) segments of C8α and C9.

Similar Datasets

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