MACPF
Encyclopedia
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
that is common to the Membrane Attack Complex
Complement membrane attack complex
The membrane attack complex is typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the alternative pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane...
proteins (MAC
Complement membrane attack complex
The membrane attack complex is typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the alternative pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane...
) of complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
(C6, C7, C8α, C8β and C9
Complement component 9
Complement component 9 is a protein involved in the complement system....
) and perforin
Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
(PF). Many members of this protein family
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
are important eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
pore forming toxins
Pore forming toxins
Pore-forming toxins are protein toxins, typically , produced by bacteria, such as C.septicum and S.aureus. They are frequently cytotoxic , as they create unregulated pores in the membrane of targeted cells.-Types of PFTs:PFTs can be divided into the following subcategories:* Alpha-pore-forming...
.
The archetypal members of the family are complement C9
Complement component 9
Complement component 9 is a protein involved in the complement system....
and perforin
Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
, both of which function in human immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
. C9 functions by punching holes in the membrane of pathogenic Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. Perforin is released by cytotoxic T cells and lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
s virally infected and transformed cells. In addition perforin permits delivery of cytotoxic proteases called granyzmes 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), a family of pore forming toxins
Pore forming toxins
Pore-forming toxins are protein toxins, typically , produced by bacteria, such as C.septicum and S.aureus. They are frequently cytotoxic , as they create unregulated pores in the membrane of targeted cells.-Types of PFTs:PFTs can be divided into the following subcategories:* Alpha-pore-forming...
previously thought to only exist in bacteria.
Biological roles of MACPF domain containing proteins
To date, around 500 members of the MACPF superfamily have been identified. Many of these proteins play key roles in the plant and animal immunity.The 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 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 granyzmes A and B into target cells. Once delivered, granyzmes are able to induce apoptosis and cause target cell death.
The plant protein CAD1 functions in the plant immune response to bacterial infection.
The sea anemone
Sea anemone
Sea anemones are a group of water-dwelling, predatory animals of the order Actiniaria; they are named after the anemone, a terrestrial flower. Sea anemones are classified in the phylum Cnidaria, class Anthozoa, subclass Zoantharia. Anthozoa often have large polyps that allow for digestion of larger...
Actineria villosa uses a MACPF 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
Astrotactin
Astrotactin is a glycoprotein expressed on migrating neurons that favors adhesion to glia and migration. It is involved in regulation of adhesion during the radial migration of neurons in the developing CNS....
is involved in neural cell migration in mammals and apextrin is involved in sea urchin (Heliocidaris erythrogramma) development. Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
Torso-like protein, which controls embryonic patterning, also contains a MACPF domain. It is unknown whether the function of any of these proteins involves lytic activity.
Functionally uncharacterised MACPF proteins are sporadically distributed in bacteria. Several species of Chlamydia contain MACPF proteins. The insect pathogenic bacteria Photorhabdus luminescens
Photorhabdus luminescens
Photorhabdus luminescens is a Gammaproteobacteria, belonging to the family Enterobacteriaceae, and is a lethal pathogen of insects....
also contains a MACPF protein, however, this molecule appears non-lytic.
Structure and mechanism
The X-ray crystal structure of Plu-MACPF, a protein from the insectInsect
Insects are a class of living creatures within the arthropods that have a chitinous exoskeleton, a three-part body , three pairs of jointed legs, compound eyes, and two antennae...
pathogenic enterobacteria Photorhabdus luminescens
Photorhabdus luminescens
Photorhabdus luminescens is a Gammaproteobacteria, belonging to the family Enterobacteriaceae, and is a lethal pathogen of insects....
has been determined (figure 1).http://www.rcsb.org/pdb/explore/explore.do?structureId=2QP2 These data reveal that the MACPF domain is homologous to pore forming
Pore forming toxins
Pore-forming toxins are protein toxins, typically , produced by bacteria, such as C.septicum and S.aureus. They are frequently cytotoxic , as they create unregulated pores in the membrane of targeted cells.-Types of PFTs:PFTs can be divided into the following subcategories:* Alpha-pore-forming...
cholesterol dependent cytolysins (CDC's) from Gram positive pathogenic bacteria such as Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
(which causes gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
). The amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence identity between the two families is extremely low, and the relationship is not detectable using conventional sequnce 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
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
regions unwinding to form four amphipathic β-strands
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
that span the membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of the target cell. Like CDC's MACPF proteins are thus β-pore forming toxins that act like a molecular hole punch.
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Control of MACPF proteins
Complement regulatory proteins such as CD59CD59
Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
function as MAC inhibitors and prevent inappropriate activity of complement against self cells (Figure 3). Biochemical studies have revealed 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 the lipocalin
Lipocalin
The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids. They share limited regions of sequence homology and a common tertiary structure architecture...
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.
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Role in Human disease
Deficiency of C9, or other components of the MAC results in an increased susceptibity to diseases caused by Gram negative bacteria such as meningococcal meningitisMeningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
. Overactivity of MACPF proteins can also cause disease. Most notably, deficiency of the MAC inhibitor CD59 results in an overactivity of complement and Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
.
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
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
mediated organ damage.
The MACPF protein DBCCR1 may function as a tumour suppressor in bladder cancer
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
.
Human proteins containing this domain
C6Complement component 6
Complement component 6 is a protein that in humans is encoded by the C6 gene.Complement component 6 is a protein involved in the complement system. It is part of the membrane attack complex which can insert into the cell membrane and cause cell to lyse....
; C7
Complement component 7
Complement component 7 is a protein involved in the complement system....
; C8A; C8B; C9
Complement component 9
Complement component 9 is a protein involved in the complement system....
; FAM5B; FAM5C; MPEG1;
PRF1
External links
- James Whisstock's laboratory at Monash UniversityMonash UniversityMonash University is a public university based in Melbourne, Victoria. It was founded in 1958 and is the second oldest university in the state. Monash is a member of Australia's Group of Eight and the ASAIHL....
- Phil Bird's laboratory at Monash UniversityMonash UniversityMonash University is a public university based in Melbourne, Victoria. It was founded in 1958 and is the second oldest university in the state. Monash is a member of Australia's Group of Eight and the ASAIHL....
- Joe Trapani's laboratory at the Peter MacCallum Cancer Centre
- James Sodetz laboratory at the University of South CarolinaUniversity of South CarolinaThe University of South Carolina is a public, co-educational research university located in Columbia, South Carolina, United States, with 7 surrounding satellite campuses. Its historic campus covers over in downtown Columbia not far from the South Carolina State House...
- The SMART MACPF protein family page
- The pfam MACPF protein family page
- Ethan Michael Smith Foundation provides information for people with HLH and related disorders
- The Histiocytosis Association of America
- The Histiocytosis Research Trust in the UK