Misplaced Pages

#985014

23-553: Archetypal members of the family are complement C9 and perforin , both of which function in human immunity . C9 functions by punching holes in the membranes of Gram-negative bacteria. Perforin is released by cytotoxic T cells and lyses virally infected and transformed cells. In addition, perforin permits delivery of cytotoxic proteases called granzymes that cause cell death . Deficiency of either protein can result in human disease. Structural studies reveal that MACPF domains are related to cholesterol-dependent cytolysins (CDCs),

46-542: A MACPF protein, however, this molecule appears non-lytic. The X-ray crystal structure of Plu-MACPF, a protein from the insect pathogenic enterobacteria Photorhabdus luminescens has been determined (figure 1). [5] These data reveal that the MACPF domain is homologous to pore forming cholesterol dependent cytolysins (CDC's) from gram-positive pathogenic bacteria such as Clostridium perfringens (which causes gas gangrene ). The amino acid sequence identity between

69-406: A bacterial MACPF protein, Plu-MACPF from Photorhabdus luminescens was determined ( PDB : 2QP2 ​). The MACPF domain is structurally similar to pore-forming cholesterol-dependent cytolysins from gram-positive bacteria , suggesting that MACPF proteins create pores and disrupt cell membranes similar to cytolysin. A representative list of proteins belonging to the MACPF family can be found in

92-443: A family of pore forming toxins previously thought to only exist in bacteria. As of early 2016, there are three families belonging to the MACPF superfamily: Proteins containing MACPF domains play key roles in vertebrate immunity, embryonic development, and neural-cell migration. The ninth component of complement and perforin form oligomeric pores that lyse bacteria and kill virus-infected cells, respectively. The crystal structure of

115-627: A large pore that punches a hole in the outer membrane of gram-negative bacteria . Perforin is stored in granules within cytotoxic T-cells and is responsible for killing virally infected and transformed cells. Perforin functions via two distinct mechanisms. Firstly, like C9, high concentrations of perforin can form pores that lyse cells. Secondly, perforin permits delivery of the cytotoxic granzymes A and B into target cells. Once delivered, granzymes are able to induce apoptosis and cause target cell death. The plant protein CAD1 ( TC# 1.C.39.11.3 ) functions in

138-431: A myth or that conditions including low temperatures, low lighting, abundance of blood, time on battlefield, presence of specific vegetation, presence of rain and humidity, and the time to organize medical evacuation would prevent the phenomenon from recurring in current conditions. P. luminescens ' genome has been sequenced . It contains a MACPF protein, however, this molecule appears non-lytic. It also contains

161-402: A proteic toxin through the expression of a single gene called makes caterpillars floppy (mcf). It also secretes enzymes which break down the body of the infected insect and bioconvert it into nutrients which can be used by both nematode and bacteria. In this way, both organisms gain enough nutrients to replicate (or reproduce in the case of the nematode) several times. The bacteria enter

184-613: Is bioluminescent ; however, the reason for this is not yet properly understood. It has been reported that infection by this bacterium of the wounds of soldiers in the American Civil War at the Battle of Shiloh caused the wounds to glow, and that this aided the survival of the soldiers due to the production of antibiotics by P. luminescens . This led to the phenomenon's nickname "Angel's Glow." There are no contemporary accounts of this phenomenon, meaning that it may be

207-456: Is a Gammaproteobacterium of the family Morganellaceae , and is a lethal pathogen of insects . It lives in the gut of an entomopathogenic nematode of the family Heterorhabditidae . When the nematode infects an insect, P. luminescens is released into the blood stream and rapidly kills the insect host (within 48 hours) by producing toxins, such as the high molecular weight insecticidal protein complex Tca. P. luminescens also produces

230-399: Is a MACPF protein involved in the complement system , which is part of the innate immune system . Once activated, about 12-18 molecules of C9 polymerize to form pores in target cell membranes , causing lysis and cell death. C9 is one member of the complement membrane attack complex (MAC), which also includes complement components C5b , C6 , C7 and C8 .   The formation of

253-541: Is involved in sea urchin ( Heliocidaris erythrogramma ) development. Drosophila Torso-like protein ( TC# 1.C.39.15.1 ), which controls embryonic patterning, also contains a MACPF domain. Its function is implicated in a receptor tyrosine kinase signaling pathway that specifies differentiation and terminal cell fate. Functionally uncharacterised MACPF proteins are sporadically distributed in bacteria. Several species of Chlamydia contain MACPF proteins. The insect pathogenic bacteria Photorhabdus luminescens also contains

SECTION 10

#1732780263986

276-596: The Transporter Classification Database . Many proteins belonging to the MACPF superfamily play key roles in plant and animal immunity. Complement proteins C6-C9 all contain a MACPF domain and assemble into the membrane attack complex. C6, C7 and C8β appear to be non-lytic and function as scaffold proteins within the MAC. In contrast both C8α and C9 are capable of lysing cells. The final stage of MAC formation involves polymerisation of C9 into

299-408: The lipocalin family and interacts with C8α. The binding site on C8α is known, however, the precise role of C8γ in the MAC remains to be understood. Deficiency of C9, or other components of the MAC results in an increased susceptibility to diseases caused by gram-negative bacteria such as meningococcal meningitis . Overactivity of MACPF proteins can also cause disease. Most notably, deficiency of

322-549: The membrane of the target cell. Like CDC's MACPF proteins are thus β-pore forming toxins that act like a molecular hole punch. Other crystal structures for members of the MACPF superfamily can be found in RCSB: i.e., 3KK7 ​, 3QOS ​, 3QQH ​, 3RD7 ​, 3OJY ​ Complement regulatory proteins such as CD59 function as MAC inhibitors and prevent inappropriate activity of complement against self cells (Figure 3). Biochemical studies have revealed

345-895: The MAC inhibitor CD59 results in an overactivity of complement and Paroxysmal nocturnal hemoglobinuria . Perforin deficiency results in the commonly fatal disorder familial hemophagocytic lymphohistiocytosis (FHL or HLH). This disease is characterised by an overactivation of lymphocytes which results in cytokine mediated organ damage. The MACPF protein DBCCR1 may function as a tumor suppressor in bladder cancer . C6 ; C7 ; C8A ; C8B ; C9 ; FAM5B ; FAM5C ; MPEG1 ; PRF1 Complement component 9 5FMW 735 12279 ENSG00000113600 ENSMUSG00000022149 P02748 P06683 NM_001737 NM_013485 NM_001368420 NM_001368421 NP_001728 NP_038513 NP_001355349 NP_001355350 Complement component 9 ( C9 )

368-491: The MAC occurs through three distinct pathways: the classical, alternative, and lectin pathways. Pore formation by C9 is an important way that bacterial cells are killed during an infection, and the target cell is often covered in multiple MACs. The clinical impact of a deficiency in C9 is an infection with the gram-negative bacterium Neisseria meningitidis . C9 genes include 11 exons and 10 introns when found in fish. In fish,

391-406: The liver is the site where the majority of complement components are produced and expressed, but C9 can also be found in other tissues. It is a single-chain glycoprotein with a four domain structure arranged in a globular bundle. MAC formation starts with the assembly of a tetrameric complex with the complement components C6, C7, C8, and C5b. The final step of MAC on target cell surfaces involves

414-454: The nematode progeny as they develop. 3,5-Dihydroxy-4-isopropyl-trans-stilbene is produced by P. luminescens bacterial symbiont of the nematode Heterorhabditis megidis . Experiments with Galleria mellonella infected larvae supports the hypothesis that the compound has antibiotic properties that help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver. P. luminescens

437-463: The peptide sequences in C8α and C9 that bind to CD59. Analysis of the MACPF domain structures reveals that these sequences map to the second cluster of helices that unfurl to span the membrane. It is therefore suggested that CD59 directly inhibits the MAC by interfering with conformational change in one of the membrane spanning regions. Other proteins that bind to the MAC include C8γ. This protein belongs to

460-516: The plant immune response to bacterial infection. The sea anemone Actineria villosa uses a MACPF (AvTX-60A; TC# 1.C.39.10.1 )protein as a lethal toxin. MACPF proteins are also important for the invasion of the Malarial parasite into the mosquito host and the liver. Not all MACPF proteins function in defence or attack. For example, astrotactin-1 ( TC# 9.B.87.3.1 ) is involved in neural cell migration in mammals and apextrin ( TC# 1.C.39.7.4 )

483-465: The polymerization of C9 molecules bound to C5b8 forming C5b-9. C9 molecules allow cylindrical, asymmetrical transmembrane pores to form. The overall complex belongs to MAC/perforin-like (MACPF)/CDC superfamily. Pore formation involves binding the C9 molecules to the target membrane, membrane molecules forming a pre-pore shape, and conformational change in the TMH1, the first transmembrane region, and TMH2,

SECTION 20

#1732780263986

506-481: The second transmembrane region. The formations of pores leads to the killing of foreign pathogens and infected host cells. C9 was found to be the most strongly under expressed serum protein in men who achieved longevity, compared to men who did not. This immunology article is a stub . You can help Misplaced Pages by expanding it . Photorhabdus luminescens Xenorhabdus luminescens Photorhabdus luminescens (previously called Xenorhabdus luminescens )

529-478: The two families is extremely low, and the relationship is not detectable using conventional sequence based data mining techniques. It is suggested that MACPF proteins and CDCs form pores in the same way (figure 1). Specifically it is hypothesised that MACPF proteins oligomerise to form a large circular pore (figure 2). A concerted conformational change within each monomer then results in two α-helical regions unwinding to form four amphipathic β-strands that span

#985014