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The Molecular Basis for Perforin Oligomerization and Transmembrane Pore Assembly

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The Molecular Basis for Perforin Oligomerization and Transmembrane Pore Assembly Immunity Article The Molecular Basis for Perforin Oligomerization and Transmembrane Pore Assembly Katherine Baran,1 Michelle Dunstone,2,3 Jenny Chia,1 Annette Ciccone,1 Kylie A. Browne,1 Christopher J.P. Clarke,1,5 Natalya Lukoyanova,8 Helen Saibil,8 James C. Whisstock,2,4 Ilia Voskoboinik,1,6,9,* and Joseph A. Trapani1,2,7,9,* 1Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia 2Department of Biochemistry and Molecular Biology 3Department of Microbiology 4ARC Centre of Excellence in Structural and Functional Microbial Genomics Monash University, Clayton, Victoria 3800, Australia 5Department of Pathology 6Department of Genetics 7Department of Microbiology and Immunology The University of Melbourne, Parkville, Victoria 3010, Australia 8Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK 9These authors contributed equally to this work *Correspondence: [email protected] (I.V.), [email protected] (J.A.T.) DOI 10.1016/j.immuni.2009.03.016 SUMMARY effector molecule of CTL and cooperates with proapoptotic serine proteases (granzymes) to induce cell death. Granzymes Perforin, a pore-forming protein secreted by cyto- may enter the target cell independently of PRF through fluid- toxic lymphocytes, is indispensable for destroying phase endocytosis after initially binding to the target cell virus-infected cells and for maintaining immune membrane electrostatically (Bird et al., 2005; Trapani et al., homeostasis. Perforin polymerizes into transmem- 2003). However, the pore-forming activity of PRF is critical for brane channels that inflict osmotic stress and facili- the regulated access of granzymes to the cytosol, where they tate target cell uptake of proapoptotic granzymes. cleave key substrates to initiate apoptotic death (Froelich et al., 1996; Nakajima et al., 1995; Shi et al., 1997). PRF is essential Despite this, the mechanism through which perforin for all granule-mediated cytotoxicity, as has been extensively monomers self-associate remains unknown. Our demonstrated in gene-targeted PRF-deficient mice (Kagi et al., current study establishes the molecular basis for per- 1994) and in humans, where congenital PRF deficiency results forin oligomerization and pore assembly. We show in the potentially fatal immunoregulatory disorder, type 2 familial that after calcium-dependent membrane binding, haemophagocytic lymphohistiocytosis (FHL) (Stepp et al., 1999; direct ionic attraction between the opposite faces of Voskoboinik et al., 2006). Incomplete loss of PRF function has adjacent perforin monomers was necessary for pore also been linked to hematological cancer (Clementi et al., 2005; formation. By using mutagenesis, we identified the Mehta et al., 2006; Voskoboinik et al., 2007), although the findings opposing charges on residues Arg213 (positive) and remain controversial and a feasible mechanism to explain the Glu343 (negative) to be critical for intermolecular association is still lacking. In other experimental scenarios, PRF interaction. Specifically, disrupting this interaction appears to be a critical mediator of tissue damage, for instance the auto-immune beta cell destruction that results in juvenile- had no effect on perforin synthesis, folding, or traf- onset (type 1) diabetes in nonobese diabetic mice (Kagi et al., ficking in the killer cell, but caused a marked kinetic 1997). defect of oligomerization at the target cell membrane, Despite its function in regulating immune homeostasis and its severely disrupting lysis and granzyme B-induced critical role in viral immunity, PRF’s molecular function remains apoptosis. Our study provides important insights poorly understood, and predictions on the functional significance into perforin’s mechanism of action. of certain of its subdomains have never been experimentally tested. For more than two decades, PRF has been known to share sequence and antigenic similarity with lytic proteins of the INTRODUCTION complement membrane attack complex (MAC) (Tschopp et al., 1986; Young et al., 1986a). The electron microscopic appear- The granule exocytosis pathway is used by cytotoxic lympho- ances of PRF and MAC pores were also shown to be quite similar cytes (CTL or NK cells) to bring about the death of virus-infected (Blumenthal et al., 1984; Dennert and Podack, 1983; Masson or transformed cells (Bolitho et al., 2007). After the formation of an and Tschopp, 1985; Podack and Dennert, 1983; Young et al., immune synapse, CTL secretory granules polarize to the site of 1986a). The major area of sequence similarity between PRF contact with the target cell, fuse with the CTL cell membrane, and MAC proteins was aptly named the membrane attack and release their luminal contents into the synapse (Stinchcombe complex-perforin (MACPF) domain, reflecting the fact that no and Griffiths, 2007; Trapani, 1998). Perforin (PRF) is a crucial other known proteins possessed such a domain (Kwon et al., 684 Immunity 30, 684–695, May 22, 2009 ª2009 Elsevier Inc. Immunity Pore Formation by Lymphocyte Perforin 1989; Lichtenheld et al., 1988; Shinkai et al., 1988). Soon after of individual FHL-associated mutations and polymorphisms this, the members of this protein family were proposed to insert (Voskoboinik et al., 2005b) and to map the key residues in the into the target cell membrane via two closely adjacent amphi- PRF C2 domain responsible for calcium-dependent membrane pathic a-helical motifs in the MACPF region, and this view of binding (Voskoboinik et al., 2005a), a mandatory step that pore formation has remained dogma ever since (Peitsch et al., precedes membrane insertion and oligomerization. 1990; Shinkai et al., 1988). Our previous studies have shown that only 20% of missense Despite the suggested importance of the proposed amphi- PRF mutations identified in FHL patients specifically affect PRF’s pathic a helices, a lack of suitable methodologies for expressing function at the level of the target cell (and are therefore termed and purifying PRF and indeed other MACPF family members has ‘‘postsynaptic’’ mutations), whereas the majority map presynap- meant that direct testing of their function during pore formation tically; that is, they map to the CTL and produce deleterious has not been feasible. However, we have now developed robust effects on protein folding or trafficking to CTL secretory granules, and validated expression systems for purifying recombinant PRF resulting in protein degradation (Voskoboinik et al., 2005b). The and also for examining its function in the context of an intact CTL current study aimed to understand the basis for PRF’s interac- (Voskoboinik et al., 2004, 2005a, 2005b), enabling us to revisit this tion with the target cell membrane, so our initial step was to issue. It has also become apparent of late that the MACPF identify those mutations that resulted in postsynaptic defects domain is far more widely distributed in nature than previously of function. We performed an initial screen of 37 missense suspected, with evolutionary conservation of the MACPF fold mutations at any of 17 charged or polar residues in this region, extending back as far as the pore-forming toxins of bacteria by expressing PRF in RBL-2H3 cells (Shiver and Henkart, 1991). (Rosado et al., 2007). Publication of the first two crystal structures These residues have previously been thought to form the internal of MACPF proteins human C8a (Hadders et al., 2007; Slade et al., ‘‘aqueous’’ surface of the PRF pore. 2008) and bacterial Plu-MACPF (a putative toxin synthesized Three distinct types of outcome were noted with respect to by Photorhabdus luminescens)(Rosado et al., 2007) provided protein expression and PRF-dependent cytotoxicity (summa- a considerable advance in our ability to predict structure-function rized in Table S1 available online and Figure 1A). The smallest relationships for PRF (Rosado et al., 2008). The structural data but most interesting group of mutations (n = 6) produced post- also revealed that the MACPF domain was much larger than orig- synaptic dysfunctions, but these all occurred at one of only inally suspected (350 amino acids) and predicted that folding two of the 17 amino acids tested, residues R213 and D191. occurred almost identically to another family of bacterial pore- These mutations underwent further characterization and, as forming toxins, the cholesterol-dependent cytolysins (CDCs). described below, turned out to provide major insights on the These recent structural findings are also revolutionary because mechanism of PRF polymerization. A second, more common they reveal that many human pathogens (for instance, Clos- outcome (n = 14) was presynaptic dysfunction, which we have tridium, Streptococcus, Chlamydia) secrete pore-forming toxins previously defined as reduced expression and/or PRF degrada- that fold through a similar molecular mechanism as the very tion or truncation in the RBL cells (Voskoboinik et al., 2004). As proteins elaborated by the immune system to eliminate them. was observed previously with FHL-associated mutations (Ishii In the present study, we performed a comprehensive functional et al., 2005; Voskoboinik et al., 2005b), this group of substitutions analysis to investigate the molecular mechanism of PRF pore invariably led to a marked loss of function (Table S1). Most formation. We definitively demonstrated that the highly conserved commonly, presynaptic dysfunction occurred at residues that amphipathic a-helical
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