Pore-forming proteins: From defense factors to endogenous executors of cell death

Pore-forming proteins (PFPs) and small antimicrobial peptides (AMPs) represent a large family of molecules with the common ability to punch holes in cell membranes to alter their permeability. They play a fundamental role as infectious bacteria's defensive tools against host's immune system and as executors of endogenous machineries of regulated cell death in eukaryotic cells. Despite being highly divergent in primary sequence and 3D structure, specific folds of pore-forming domains have been conserved. In fact, pore formation is considered an ancient mechanism that takes place through a general multistep process involving: membrane partitioning and insertion, oligomerization and pore formation. However, different PFPs and AMPs assemble and form pores following different mechanisms that could end up either in the formation of protein-lined or protein-lipid pores. In this review, we analyze the current findings in the mechanism of action of different PFPs and AMPs that support a wide role of membrane pore formation in nature. We also provide the newest insights into the development of state-of-art techniques that have facilitated the characterization of membrane pores. To understand the physiological role of these peptides/proteins or develop clinical applications, it is essential to uncover the molecular mechanism of how they perforate membranes.