Sleuths solve one puzzle in the mystery of bacterial persistence
This afternoon, reading through Professor Kim Lewis’ soon to be published article in Cell Press (available ahead of print here), I may have fancied myself something of a private investigator with the high stakes job of providing a comprehensive picture of his new findings for you, my dedicated reader. It was a pretty action-heavy couple of hours, despite the apparent silence in my lonely office. There were high-speed chases, but no cars were involved. Only protein kinases and antibiotic resistance.
Now that it’s all over, I think I have a good package to present you with. While I don’t have a manila envelope full of sleuthed photos taken with a wide angle lens, I hope you’ll still be convinced.
So, here’s what I found out:
Bacteria, as you may know, have a tendency to develop antibiotic resistance. How they do it is a mystery that has compelled actual scientific investigators for decades. In 1983, one team of said investigators identified a protein critical to what Lewis calls “persistence” — the ability of a bacterial cell to “sleep” through an antibiotic attack and “wake up” unharmed, ready to infect the host anew.
Under normal growth conditions, HipA, as this protein is called, is turned off by virtue of being bound to another protein called HipB (obviously). When HipA gets turned on, it starts running around the cell snatching up proteins important to cell growth and turning them off, which puts the cell into a kind of hibernation.
Previous work had suggested that HipA gets turned on when a certain “sweet spot” is tagged with a chemical group called a “phosphate.” But this didn’t make much sense because getting a phosphate to that sweet spot was like trying to mix oil and water….literally: the spot is buried in a hydrophobic core while the phosphate is hydrophillic.
Lewis’ group decided to take a closer look at pHipA (HipA tagged with a phosphate group). Just like zooming in to find Jessica Rabbit playing patty-cake with Marv Acme, this revealed more than they were expecting.
In this bound form, that sweet spot is actually pulled out of the hydrophobic core, exposing it to an area much friendlier to water-loving stuff like phosphates. That explained how HipA got phosphorylated in the first place, but it created a whole new mystery: now, instead of being buried in a vat of oil, so to speak, the sweet spot completely blocks the active site making it impossible for HipA to do it’s job. Instead of being the “on” version of the protein, pHipA is actually another kind of “off” version, contrary to what researchers had been thinking.
This new understanding of the protein’s structure allowed Lewis’ team to come up with a scheme for how HipA regulates persistence:
First, HipA is turned off because it’s bound to HipB. The bacterial cell grows and reproduces normally. Then, for one reason or another, HipA breaks away from HipB and becomes active, sending the cell into hibernation. The sweet spot swings in and out of the hydrophobic core and if it happens to get tagged with a phosphate group, that shuts down HipA’s activity and the cell is able to wake up again.
It’s still unclear exactly what happens after HipA gets phosphorylated. Does it break down completely or can it gradually get de-phosphorylated? This is where more work will need to be done.
Which is good, because I think I’ve filled you with enough evidence for one post. Stay tuned for more adventures in the life of this international woman of mystery…