The membrane attack complex/perforin (MACPF) domain is conserved in bacteria, fungi, mammals and plants. It was originally identified and named as being common to five complement components (C6, C7, C8-alpha, C8-beta, and C9) and perforin. These molecules perform critical functions in innate and adaptive immunity. The MAC family proteins and perforin are known to participate in lytic pore formation. In response to pathogen infection, a sequential and highly specific interaction between the constituent elements occurs to form transmembrane channels which are known as the membrane-attack complex (MAC).Only a few other MACPF proteins have been characterised and several are thought to form pores for invasion or protection [ (PUBMED:16900325) (PUBMED:17717151) (PUBMED:18440555) ]. Examples are proteins from malarial parasites [ (PUBMED:15659064) ], the cytolytic toxins from sea anemones [ (PUBMED:17368498) ], and proteins that provide plant immunity [ (PUBMED:16900325) (PUBMED:15799997) ]. Functionally uncharacterised MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp [ (PUBMED:10608922) ] and Photorhabdus luminescens (Xenorhabdus luminescens) [ (PUBMED:17717151) ].
The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 LDLRA EGF-like,Sushi/CCP/SCR FIMAC or C2. They probably control or target MACPF function [ (PUBMED:17717151) (PUBMED:17872444) ]. The MACPF domain oligomerizes, undergoes conformational change, and is required for lytic activity.
The MACPF domain consists of a central kinked four-stranded antiparallel beta sheet surrounded by alpha helices and beta strands, forming two structural segments. Overall, the MACPF domain has a thin L-shaped appearance. MACPF domains exhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif [ (PUBMED:17717151) (PUBMED:18440555) (PUBMED:17872444) ].
Some proteins known to contain a MACPF domain are listed below:
Vertebrate complement proteins C6 to C9. Complement factors C6 to C9 assemble to form a scaffold, the membrane attack complex (MAC), that permits C9 polymerisation into pores that lyse Gram-negative pathogens [ (PUBMED:18440555) (PUBMED:17872444) ].
Vertebrate perforin. It is delivered by natural killer cells and cytotoxic T lymphocytes and forms oligomeric pores (12 to 18 monomers) in the plasma membrane of either virus-infected or transformed cells.
Arabidopsis thaliana (Mouse-ear cress) constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognises plant signals for pathogen infection [ (PUBMED:15799997) ].
Plasmodium sporozoite microneme protein essential for cell traversal 2 (SPECT2). It is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection [ (PUBMED:15659064) ].
P. luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes [ (PUBMED:17717151) ].
Chlamydial putative uncharacterised protein CT153 [ (PUBMED:10608922) ].
Family alignment:
There are 3546 MACPF domains in 3539 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing MACPF domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with MACPF domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing MACPF domain in the selected taxonomic class.
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
Role of a disulfide-bonded peptide loop within human complement C9 in the species-selectivity of complement inhibitor CD59.
Biochemistry. 1996; 35: 3263-9
Display abstract
CD59 antigen is a membrane glycoprotein that inhibits the activity of the C9 component of the C5b-9 membrane attack complex (MAC), thereby protecting human cells from lysis by human complement. The complement-inhibitory activity of CD59 is species-selective, and is most effective toward C9 derived from human or other primate plasma. The species-selective activity of CD59 was recently used to map the segment of human C9 that is recognized by this MAC inhibitor, using recombinant rabbit/human C9 chimeras that retain lytic function within the MAC [Husler, T., Lockert, D. H., Kaufman, K. M., Sodetz, J. M., Sims, P. J. (1995) J. Biol. Chem. 270,3483-3486]. These experiments suggested that the CD59 recognition domain was contained between residues 334 and 415 in human C9. By analyzing the species-selective lytic activity of recombinant C9 with chimeric substitutions internal to this segment, we now demonstrate that the site in human C9 uniquely recognized by CD59 is centered on those residues contained between C9 Cys359/Cys384, with an additional contribution by residues C-terminal to this segment. Consistent with its role as a CD59 recognition domain, CD59 specifically bound a human C9-derived peptide corresponding to residues 359-384, and antibody (Fab) raised against this C9-derived peptide inhibited the lytic activity of human MAC. Mutant human C9 in which Ala was substituted for Cys359/384 was found to express normal lytic activity and to be fully inhibited by CD59. This suggests that the intrachain Cys359/Cys384 disulfide bond within C9 is not required to maintain the conformation of this segment of C9 for interaction with CD59.
Localization and molecular modelling of the membrane-inserted domain of the ninth component of human complement and perforin.
Mol Immunol. 1990; 27: 589-602
Display abstract
Upon interaction with the membrane-bound C5b-8 complex, the ninth component of complement (C9) unfolds and inserts into the membrane of cells on which surface complement has been activated. Consequently C9 oligomerization occurs and transmembrane channels of varying sizes are formed. The domain of the unfolded protein interacting with the cell membrane has so far not been identified since, unlike many integral membrane proteins, the C9 sequence does not contain a continuous stretch of hydrophobic amino acids. We studied the interaction of C9 with the lipid bilayer using the membrane-restricted photoaffinity label 3-(trifluoromethyl)-3-(m[125I]iodophenyl)diazirine (125I-TID). C9 was assembled on liposomes and after photoactivation, several labeled and non-labeled peptides, obtained by chemical and enzymatic cleavage or the 125I-TID-labeled C9, were analyzed. The segment from 176 to 345 was identified as the region containing the membrane-interacting structure. By means of secondary structure predictions, we identified two amphipathic alpha-helices (292-308 and 313-333) separated by a turn (309-312). Based on these results, we constructed a molecular model for the membrane-spanning region of C9. By analogy, we also constructed a model for this domain in perforin/cytolysin, a pore-forming protein found in the cytoplasmic granules of cytotoxic T-lymphocytes.
Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the MACPF domain.
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with MACPF domain which could be assigned to a KEGG orthologous group, and not all proteins containing MACPF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
