Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity

Area of Science:

• Immunology
• Cell Biology
• Structural Biology

Background:

• Perforin-2 (MPEG1) is crucial for macrophage-mediated killing of intracellular bacteria.
• Loss of perforin-2 function increases susceptibility to bacterial infections.
• The precise mechanism of perforin-2 activation and pore formation remains unclear.

Purpose of the Study:

• To elucidate the atomic-level mechanism of perforin-2 activation and pore formation.
• To understand how perforin-2 avoids premature self-attack.

Main Methods:

• Atomic structures of pre-pore and pore assemblies
• High-speed atomic force microscopy
• Functional assays

Main Results:

• Perforin-2 forms a pre-pore complex with distinct membrane-targeting and pore-forming domains.
• Acidification induces a 180° conformational change, triggering pore assembly.
• This mechanism prevents premature pore formation and bacterial lysis.

Conclusions:

• Perforin-2 activation is regulated by acidification via a novel conformational switch.
• This mechanism ensures targeted bacterial killing by phagocytes.
• The findings offer insights into the evolution of perforin family proteins and innate immunity.