Pore-forming proteins as drivers of membrane permeabilization in cell death pathways

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Regulated cell death (RCD) involves pore-forming proteins (PFPs) executing specific pathways.
• Key PFPs include BAX/BAK/BOK (apoptosis), gasdermins (GSDMs, pyroptosis), and MLKL (necroptosis).
• PFPs transition from inactive precursors to active, membrane-inserted states via complex mechanisms.

Purpose of the Study:

• To review the structural rearrangements and activation mechanisms of RCD-related PFPs.
• To describe pore formation and maturation by BAX/BAK/BOK, GSDMs, and MLKL.
• To highlight commonalities and differences in PFP mechanisms and discuss implications of coexisting cell death modalities.

Main Methods:

• Literature review of structural biology and cell death research.
• Analysis of protein activation, membrane interaction, and pore assembly mechanisms.
• Comparative analysis of BAX/BAK/BOK, GSDM, and MLKL pathways.

Main Results:

• PFPs undergo conformational changes for membrane recruitment, insertion, and oligomerization.
• Diverse pore architectures are formed by different PFP families.
• Shared and distinct mechanisms govern PFP activation and function.

Conclusions:

• Understanding PFP structural dynamics is crucial for elucidating RCD pathways.
• The interplay between different RCD modalities has significant physiological and pathophysiological consequences.
• Further research into PFP mechanisms can reveal therapeutic targets for diseases involving aberrant cell death.