Animation of the Perforin-2 (MPEG1) subunits, arcs and complete bactericidal pore at high resolution.

2020-07-03T16:40:20Z (GMT) by George Munson
Animation of the murine Perforin-2 (MPEG1) pore. Perforin-2 is constitutively expressed in macrophages and other phagocytes. It plays an essential role in the destruction of microbes by permeabilizing the envelope of phagocytosed bacteria. This animations was rendered from PDB file 6SB5 with UCSF Chimera (https://www.cgl.ucsf.edu/chimera/). Movies were captured with macOS Catalina applications Screenshot and Quicktime.

Supports Publication: Ni, T., Jiao, F., Yu, X., Aden, S., Ginger, L., Williams, S. I., Bai, F., Pražák, V., Karia, D., Stansfeld, P., Zhang, P., Munson, G., Anderluh, G., Scheuring, S., & Gilbert, R. J. C. (2020). Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity. Science Advances, 6(5), eaax8286. https://doi.org/10.1126/sciadv.aax8286

Publication 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.