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Instruments / Technical Area	Publication Details	Published	Actions
Krios I-Titan Krios I at Diamond	Cryo‐EM structures of perforin‐2 in isolation and assembled on a membrane suggest a mechanism for pore formation Xiulian Yu , Tao Ni , George Munson , Peijun Zhang , Robert J. C. Gilbert The Embo Journal 11 DOI: 10.15252/embj.2022111857 Diamond Proposal Number(s): [20223, 21004] Open Access Show Abstract ▼ Abstract: Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 β-hairpin for binding to the lipid membrane surface. Overall, these structural snapshots suggest a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane, potentially using the twisted pore as an intermediate or alternative state to the flat conformation, with the capacity to cause bilayer distortion during membrane insertion.	Oct 2022
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity Tao Ni , Fang Jiao , Xiulian Yu , Saša Aden , Lucy Ginger , Sophie I. Williams , Fangfang Bai , Vojtech Prazak , Dimple Karia , Phillip Stansfeld , Peijun Zhang , George Munson , Gregor Anderluh , Simon Scheuring , Robert J. C. Gilbert Science Advances 6 DOI: 10.1126/sciadv.aax8286 Show Abstract ▼ Abstract: Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.	Jan 2020

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