Structural Biology of the Membrane Attack Complex

Sonnen, Andreas F.‐P.; Henneke, Philipp

doi:10.1007/978-94-017-8881-6_6

Cited by 23 publications

(14 citation statements)

References 183 publications

(272 reference statements)

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“…Most of them localize in the membrane attack complex perforin domain (MACPF) ( Fig. 3G) and in particular in two functional regions that integrate into the plasma membrane (TMH elements) (Sonnen & Henneke 2014). In C9, one of these regions is targeted by the paramyosin of Schistosoma mansoni (Deng et al 2003); a positively selected site (A390) in humans is also part of the primary CD59 recognition site (Huang et al 2006).…”

Section: Positive Selection At Interaction Surfacesmentioning

confidence: 99%

The mammalian complement system as an epitome of host–pathogen genetic conflicts

et al. 2016

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The complement system is an innate immunity effector mechanism; its action is antagonized by a wide array of pathogens and complement evasion determines the virulence of several infections. We investigated the evolutionary history of the complement system and of bacterial-encoded complement-interacting proteins. Complement components targeted by several pathogens evolved under strong selective pressure in primates, with selection acting on residues at the contact interface with microbial/viral proteins. Positively selected sites in CFH and C4BPA account for the human specificity of gonococcal infection. Bacterial interactors, evolved adaptively as well, with selected sites located at interaction surfaces with primate complement proteins. These results epitomize the expectation under a genetic conflict scenario whereby the host's and the pathogen's genes evolve within binding avoidance-binding seeking dynamics. In silico mutagenesis and protein-protein docking analyses supported this by showing that positively selected sites, both in the host's and in the pathogen's interacting partner, modulate binding.

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Section: Positive Selection At Interaction Surfacesmentioning

confidence: 99%

The mammalian complement system as an epitome of host–pathogen genetic conflicts

et al. 2016

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“…The complement membrane attack complex is however different from the CDCs and perforin in that its membrane binding depends on the activation and formation of a nucleating C5b-8 complex of proteins. This complex then attracts multiple copies of the principal pore-forming subunit, C9 (Aleshin et al 2012 ; Sonnen and Henneke 2014 ). There may not be a pre-pore oligomeric state for the MAC, in contrast to the CDCs and perforin (Aleshin et al 2012 ; Sonnen and Henneke 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Measuring kinetic drivers of pneumolysin pore structure

Gilbert

Sonnen

2016

Eur Biophys J

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Most membrane attack complex-perforin/cholesterol-dependent cytolysin (MACPF/CDC) proteins are thought to form pores in target membranes by assembling into pre-pore oligomers before undergoing a pre-pore to pore transition. Assembly during pore formation is into both full rings of subunits and incomplete rings (arcs). The balance between arcs and full rings is determined by a mechanism dependent on protein concentration in which arc pores arise due to kinetic trapping of the pre-pore forms by the depletion of free protein subunits during oligomerization. Here we describe the use of a kinetic assay to study pore formation in red blood cells by the MACPF/CDC pneumolysin from Streptococcus pneumoniae. We show that cell lysis displays two kinds of dependence on protein concentration. At lower concentrations, it is dependent on the pre-pore to pore transition of arc oligomers, which we show to be a cooperative process. At higher concentrations, it is dependent on the amount of pneumolysin bound to the membrane and reflects the affinity of the protein for its receptor, cholesterol. A lag occurs before cell lysis begins; this is dependent on oligomerization of pneumolysin. Kinetic dissection of cell lysis by pneumolysin demonstrates the capacity of MACPF/CDCs to generate pore-forming oligomeric structures of variable size with, most likely, different functional roles in biology.

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“…C8B is a subunit of complement component 8 (C8) protein. C8 is a component of the membrane attack complex (MAC), which plays a key role in the innate and adaptive immune system by mediating cell lysis [ 61 ]. KLKB1 (kallikrein B) is also a plasma protein secreted by the liver.…”

Section: Discussionmentioning

confidence: 99%

Identification of CTLA2A, DEFB29, WFDC15B, SERPINA1F and MUP19 as Novel Tissue-Specific Secretory Factors in Mouse

et al. 2015

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Secretory factors in animals play an important role in communication between different cells, tissues and organs. Especially, the secretory factors with specific expression in one tissue may reflect important functions and unique status of that tissue in an organism. In this study, we identified potential tissue-specific secretory factors in the fat, muscle, heart, lung, kidney and liver in the mouse by analyzing microarray data from NCBI’s Gene Expression Omnibus (GEO) public repository and searching and predicting their subcellular location in GeneCards and WoLF PSORT, and then confirmed tissue-specific expression of the genes using semi-quantitative PCR reactions. With this approach, we confirmed 11 lung, 7 liver, 2 heart, 1 heart and muscle, 7 kidney and 2 adipose and liver-specific secretory factors. Among these genes, 1 lung-specific gene - CTLA2A (cytotoxic T lymphocyte-associated protein 2 alpha), 3 kidney-specific genes - SERPINA1F (serpin peptidase inhibitor, Clade A, member 1F), WFDC15B (WAP four-disulfide core domain 15B) and DEFB29 (defensin beta 29) and 1 liver-specific gene - MUP19 (major urinary protein 19) have not been reported as secretory factors. These genes were tagged with hemagglutinin at the 3’end and then transiently transfected to HEK293 cells. Through protein detection in cell lysate and media using Western blotting, we verified secretion of the 5 genes and predicted the potential pathways in which they may participate in the specific tissue through data analysis of GEO profiles. In addition, alternative splicing was detected in transcripts of CTLA2A and SERPINA1F and the corresponding proteins were found not to be secreted in cell culture media. Identification of novel secretory factors through the current study provides a new platform to explore novel secretory factors and a general direction for further study of these genes in the future.

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Structural Biology of the Membrane Attack Complex

Cited by 23 publications

References 183 publications

The mammalian complement system as an epitome of host–pathogen genetic conflicts

The mammalian complement system as an epitome of host–pathogen genetic conflicts

Measuring kinetic drivers of pneumolysin pore structure

Identification of CTLA2A, DEFB29, WFDC15B, SERPINA1F and MUP19 as Novel Tissue-Specific Secretory Factors in Mouse

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