E. coli Infection

Reference

Zhang et al. “A genetically incorporated crosslinker reveals chaperone cooperation in acid resistance.” Nature Chemical Biology (2011) 7, pgs 671 – 677

                For the Gram-negative bacterium Escherichia coli to successfully infect a victim following ingestion, it must survive a trip through the stomach and reach the small intestine.  Mammalian stomachs create a low pH environment to help break down incoming proteins from both food eaten and any accidently ingested pathogens.  Unfortunately, several enteric bacteria, including some strains of E. coli, are able to survive the acidic stomach to arrive at the neutral small intestine intact and successfully infect a victim.

                The outer membranes of Gram-negative bacteria are quite porous and will allow passage of molecules smaller than 600 Da.  Obviously protons can easily cross that membrane to reach the periplasmic proteins within.  How do the bacteria protect these proteins from either denaturation at low pH (stomach) or incorrect renaturation upon reaching neutral pH (small intestine)?

                It was previously known that the bacterial protein HdeA binds periplasmic bacterial proteins at low pH to protect them.  Once reaching the neutral small intestine, HdeA releases its substrates in a nonactive form that must then be properly folded again for full function.  What additional chaperones were involved in this process as well as substrates for HdeA were unknown.

                Recent work by Chen and colleagues, published last month in the journal Nature Chemical Biology, focused on identifying substrates for HdeA by using an unnatural amino acid (named DiZPK by the authors) whose side chain can photocrosslink with proximal protein.  They were able to place this version of HdeA inside living E. coli cells, subject them to low pH and thus identify substrates for HdeA.

                Interestingly, the two substrate proteins identified here are DegP and SurA, both of which are essential chaperone protein themselves.  The authors theorize that HdeA exists to protect these two important chaperones at low pH and helps refold them upon neutralization, which means they are then subsequently free to help other proteins refold (Figure 4.1, directly from their paper).  While the cytosol has mechanisms in place for chaperone protein folding mediated by ATP, the periplasmic space is low in ATP so the bacteria have developed another way to circumvent the situation.

                The importance of HdeA could lead to new therapies to treat E. coli infections.