{PDOC00251} {PS00279; MACPF_1} {PS51412; MACPF_2} {BEGIN} ************************************************************************* * Membrane attack complex/perforin (MACPF) domain signature and profile * ************************************************************************* 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 characterized and several are thought to form pores for invasion or protection [1,2,3]. Examples are proteins from malarial parasites [4], the cytolytic toxins from sea anemones [5], and proteins that provide plant immunity [1,6]. Functionally uncharacterized MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp. [7] and Photorhabdus luminescens [2]. The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 (see ), LDLRA (see ), EGF-like (see ), Sushi/CCP/SCR (see ), FIMAC or C2 (see ). They probably control or target MACPF function [2,8]. 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 (see ). MACPF domains exhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif [2,3,8]. 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 polymerization into pores that lyse Gram-negative pathogens [3,8]. - 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 constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognizes plant signals for pathogen infection [6]. - Arabidopsis thaliana necrotic spotted lesions 1 (NSL1) protein [1]. - Venomous sea anemone Phyllodiscus semoni toxins PsTX-60A and PsTX-60B [5]. - Venomous sea anemone Actineria villosa toxin AvTX-60A [5]. - 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 [4]. - Photorhabdus luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes [2]. - Chlamydial putative uncharacterized protein CT153 [7]. We developed both a pattern and a profile for the MACPF domain. Whereas the profile covers the entire MACPF domain, the pattern is based on the conserved signature of the MACPF domain. -Consensus pattern: Y-x(6)-[FY]-G-T-H-[FY] -Sequences known to belong to this class detected by the pattern: ALL, except for rabbit C8-beta. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: November 2008 / Text revised; profile added. [ 1] Noutoshi Y., Kuromori T., Wada T., Hirayama T., Kamiya A., Imura Y., Yasuda M., Nakashita H., Shirasu K., Shinozaki K. "Loss of Necrotic Spotted Lesions 1 associates with cell death and defense responses in Arabidopsis thaliana." Plant Mol. Biol. 62:29-42(2006). PubMed=16900325; DOI=10.1007/s11103-006-9001-6 [ 2] Rosado C.J., Buckle A.M., Law R.H.P., Butcher R.E., Kan W.-T., Bird C.H., Ung K., Browne K.A., Baran K., Bashtannyk-Puhalovich T.A., Faux N.G., Wong W., Porter C.J., Pike R.N., Ellisdon A.M., Pearce M.C., Bottomley S.P., Emsley J., Smith A.I., Rossjohn J., Hartland E.L., Voskoboinik I., Trapani J.A., Bird P.I., Dunstone M.A., Whisstock J.C. "A common fold mediates vertebrate defense and bacterial attack." Science 317:1548-1551(2007). PubMed=17717151; DOI=10.1126/science.1144706 [ 3] Slade D.J., Lovelace L.L., Chruszcz M., Minor W., Lebioda L., Sodetz J.M. "Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit." J. Mol. Biol. 379:331-342(2008). PubMed=18440555; DOI=10.1016/j.jmb.2008.03.061 [ 4] Ishino T., Chinzei Y., Yuda M. "A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection." Cell. Microbiol. 7:199-208(2005). PubMed=15659064; DOI=10.1111/j.1462-5822.2004.00447.x [ 5] Satoh H., Oshiro N., Iwanaga S., Namikoshi M., Nagai H. "Characterization of PsTX-60B, a new membrane-attack complex/perforin (MACPF) family toxin, from the venomous sea anemone Phyllodiscus semoni." Toxicon 49:1208-1210(2007). PubMed=17368498; DOI=10.1016/j.toxicon.2007.01.006 [ 6] Morita-Yamamuro C., Tsutsui T., Sato M., Yoshioka H., Tamaoki M., Ogawa D., Matsuura H., Yoshihara T., Ikeda A., Uyeda I., Yamaguchi J. "The Arabidopsis gene CAD1 controls programmed cell death in the plant immune system and encodes a protein containing a MACPF domain." Plant Cell Physiol. 46:902-912(2005). PubMed=15799997; DOI=10.1093/pcp/pci095 [ 7] Ponting C.P. "Chlamydial homologues of the MACPF (MAC/perforin) domain." Curr. Biol. 9:R911-R913(1999). PubMed=10608922 [ 8] Hadders M.A., Beringer D.X., Gros P. "Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense." Science 317:1552-1554(2007). PubMed=17872444; DOI=10.1126/science.1147103 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}