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The Membrane Attack Complex/Perforin (MACPF) superfamily, sometimes referred to as the MACPF/CDC superfamily, is named after a domain that is common to the
membrane attack complex The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and as such is an effecto ...
(MAC) proteins of the complement system (C6, C7, C8α, C8β and C9) and perforin (PF). Members of this
protein family A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be ...
are pore-forming toxins (PFTs). In eukaryotes, MACPF proteins play a role in immunity and development. Archetypal members of the family are complement C9 and perforin, both of which function in human
immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...
. C9 functions by punching holes in the membranes of
Gram-negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...
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 Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
. 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 previously thought to only exist in bacteria.


Families

As of early 2016, there are three families belonging to the MACPF superfamily:
1.C.12
- The Thiol-activated Cholesterol-dependent Cytolysin (CDC) Family
1.C.39
- The Membrane Attack Complex/Perforin (MACPF) Family
1.C.97
- The Pleurotolysin Pore-forming (Pleurotolysin) Family


Membrane Attack Complex/Perforin (MACPF) Family

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 a bacterial MACPF protein, Plu-MACPF from ''Photorhabdus luminescens'' was determined (). The MACPF domain is structurally similar to pore-forming cholesterol-dependent cytolysins from
gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain ...
, 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 th
Transporter Classification Database


Biological roles of MACPF domain containing proteins

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 a large pore that punches a hole in the outer membrane of
gram-negative bacteria Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelo ...
. 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 the plant immune response to bacterial infection. The
sea anemone Sea anemones ( ) are a group of predation, predatory marine invertebrates constituting the order (biology), order Actiniaria. Because of their colourful appearance, they are named after the ''Anemone'', a terrestrial flowering plant. 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 Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
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
is involved in sea urchin ('' Heliocidaris erythrogramma'') development. ''
Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
'' 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 ''Photorhabdus luminescens'' (previously called ''Xenorhabdus luminescens'') 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 Hetero ...
'' 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
insect Insects (from Latin ') are Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (Insect morphology#Head, head, ...
pathogenic
enterobacteria Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It includes over 30 genera and more than 100 species. Its classification above the level of Family (taxonomy), family is still a subject of debate, but one class ...
''
Photorhabdus luminescens ''Photorhabdus luminescens'' (previously called ''Xenorhabdus luminescens'') 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 Hetero ...
'' has been determined (figure 1

These data reveal that the MACPF domain is homologous to pore forming toxins, pore forming cholesterol dependent cytolysins (CDC's) from
gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...
pathogenic bacteria such as ''
Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, bacillus (rod-shaped), anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present ...
'' (which causes
gas gangrene Gas gangrene (also known as clostridial myonecrosis) is a bacterial infection that produces tissue gas in gangrene. This deadly form of gangrene usually is caused by '' Clostridium perfringens'' bacteria. About 1,000 cases of gas gangrene are r ...
). The
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
sequence identity between 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 In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...
β-strands that span the
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
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., , , , ,


Control of MACPF proteins

Complement regulatory proteins such as CD59 function as
MAC Mac or MAC may refer to: Common meanings * Mac (computer), a line of personal computers made by Apple Inc. * Mackintosh, a raincoat made of rubberized cloth * Mac, a prefix to surnames derived from Gaelic languages * McIntosh (apple), a Canadi ...
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 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.


Role in human disease

Deficiency of C9, or other components of the MAC results in an increased susceptibility to diseases caused by
gram-negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...
bacteria such as meningococcal
meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasion ...
. 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 (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process ...
. Perforin deficiency results in the commonly fatal disorder familial hemophagocytic lymphohistiocytosis (FHL or HLH). This disease is characterised by an overactivation of
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
which results in
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
mediated organ damage. The MACPF protein DBCCR1 may function as a tumor suppressor in
bladder cancer Bladder cancer is the abnormal growth of cells in the bladder. These cells can grow to form a tumor, which eventually spreads, damaging the bladder and other organs. Most people with bladder cancer are diagnosed after noticing blood in thei ...
.


Human proteins containing this domain

C6; C7; C8A; C8B; C9; FAM5B; FAM5C; MPEG1; PRF1


References

{{DEFAULTSORT:Macpf Protein families Membrane proteins Transmembrane proteins Transmembrane transporters Transport proteins Integral membrane proteins