Pore formation by pore forming membrane proteins towards infections

Abstract

Over the last 25 years, the biology of membrane proteins, including the PFPs-membranes interactions is seeking attention for the development of successful drug molecules against a number of infectious diseases. Pore forming toxins (PFTs), the largest family of PFPs are considered as a group of virulence factors produced in a large number of pathogenic systems which include streptococcus, pneumonia, Staphylococcus aureus, E. coli, Mycobacterium tuberculosis, group A and B streptococci, Corynebacterium diphtheria and many more. PFTs are generally utilized by the disease causing pathogens to disrupt the host first line of defense i.e. host cell membranes through pore formation strategy. Although, pore formation is the principal mode of action of the PFTs but they can have additional adverse effects on the hosts including immune evasion. Recently, structural investigation of different PFTs have imparted the molecular mechanistic insights into how PFTs get transformed from its inactive state to active toxic state. On the basis of their structural entity, PFTs have been classified in different types and their mode of actions alters in terms of pore formation and corresponding cellular toxicity. Although pathogen genome analysis can identify the probable PFTs depending upon their structural diversity, there are so many PFTs which utilize the local environmental conditions to generate their pore forming ability using a novel strategy which is known as "conformational switch" of a protein. This conformational switch is considered as characteristics of the phase shifting proteins which were often utilized by many pathogenic systems to protect them from the invaders through allosteric communication between distant regions of the protein. In this chapter, we discuss the structure function relationships of PFTs and how activity of PFTs varies with the change in the environmental conditions has been explored. Finally, we demonstrate these structural insights to develop therapeutic potential to treat the infections caused by multidrug resistant pathogens.

Keywords: Infectious disease; Membrane; Oligomers; Pore forming proteins; Protein-membrane interactions.