Structure of SpoIVFB when it is inhibited by SpoIVFA and BofA. Image credit: Michael Feig (CC BY 4.0)
Proteases are a type of protein that work by cutting up other proteins. The part of the protease that does the cutting is called the active site. Intramembrane proteases are a specific group of proteases that cut up the proteins within cell membranes. There is a lot of interest in learning how to control intramembrane proteases because they are important in regulating the signaling processes that cells use to communicate. SpoIVFB is an intramembrane protease from the bacterium Bacillus subtilis that is studied often as a model for these types of proteases.
Bacillus subtilis uses SpoIVFB to produce spores, dormant reproductive cells that can survive extreme, harsh conditions for long periods with minimal energy. SpoIVFB is part of the system that allows spores to communicate with their ‘parent cells’, the cells they develop in. The activity of this protein is blocked by two other proteins called SpoIVFA and BofA. When these proteins are destroyed, SpoIVFB becomes active, but it is unclear exactly how SpoIVFA and BofA inhibit SpoIVFB. Understanding this relationship could help to reveal ways to regulate other intramembrane proteases.
To address this question, Olenic et al. used genetic, biochemical and computer modelling techniques to study how SpoIVFB activity is regulated in Bacillus subtilis. The results show that a region of BofA blocks the area of SpoIVFB that cuts a protein called Pro-σK, which stops SpoIVFB from releasing active σK into the ‘parent cell’. By making genetic variants of BofA, Olenic et al. identified three parts of BofA that are needed to fully inhibit SpoIVFB. A computer model predicts that these three parts give BofA the right shape to inhibit SpoIVFB, and that SpoIVFA helps by forming a bridge between BofA and SpoIVFB.
This investigation reveals how the intramembrane protease SpoIVFB is regulated by SpoIVFA and BofA. This information could be useful in developing inhibitors for other intramembrane proteases. The next stage will be to make and test artificial inhibitors based on the structures studied here. If successful, these could have applications in areas such as medicine, agriculture, industry and environmental protection.
