Thursday, February 15, 2007

A Novel Wooden Shoe

It is increasingly clear that many pathogens do not simply assault our bodies, but truly attempt to infiltrate them and co-opt normal cellular processes to their ends. A number of recent papers have described kinase-based strategies employed by Plasmodium and Toxoplasma.

Protein kinases are critical players in cellular signal transduction. By attaching a phosphate group to a serine, threonine or tyrosine (and occasionally, at least known to date, histidine) they can radically change the local structure and charge distribution of the substrate protein. This can in turn trigger intramolecular rearrangements or alter protein-protein interactions, which can cascade in numerous ways. Tapping into this network is potentially a devastating way to sabotage the host's cellular machinery.

Kinases are opposed in their action by protein phosphatases, which knock the phosphates off the proteins. In most cases, kinase and phosphatase can easily interchange the states of the protein; there can be infinite back-and-forth so long as the protein sticks around. A few cases have been found where re-phosphorylation is presented by glycosylation of a residue -- the same side chain oxygen can't have both at once. But glycosylation can also be reversed, so this so-called yin-yang regulation simply adds a third possible state. A quick PubMed search reveals at least one reported example of host phosphatases being manipulated by a pathogen, albeit indirectly.

The newest Science adds a new pathogen sabot to those uncovered previously. Instead of merely stripping the phosphate off and leaving an exposed hydroxyl for re-phosphorylation, in this example the Shigella protein is a phosphothreonine lyase, an enzyme which actually modifies the side chain, abstracting both the phosphate and a hydrogen and leaving behind a double bond (see Figure 3D). Hence, the kinases so altered cannot be re-phosphorylated -- they are now permanently disabled. Since such dead proteins have the ability to tie up functional binding partners, acting as a dominant negative, this is potentially a very effective strategy. Also striking is the fact that a phospho-amino acid lyase activity had not described previously. It is difficult to believe this is the last novel biochemical strategem we will find in a pathogen's playbook.

1 comment:

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