Figure 3. Possible mechanisms for functional polymorphisms in plasmodial surface anion channel activity.

In each panel, a ‘wild-type’ channel is shown in the top bilayer, while mutant or polymorphic channels are shown on the lower membrane. Parasite-encoded channel subunits or enzymes are shown in blue, while human proteins are shown in green. Polymorphic residues are shown as red dots (plus arrowheads) on the channel protein or on modifying enzymes and can arise only on parasite-encoded proteins. (A) A parasite-encoded ion channel model can accrue multiple distinct single-nucleotide polymorphisms and yield a spectrum of channel phenotypes. (B) A human ion channel activated by a specific parasite enzyme (e.g., a kinase that phosphorylates multiple sites on the channel protein) can produce distinct patterns of activation if mutations in the enzyme yield differing affinities for the sites on the human target protein. (C) An ion channel consisting of both parasite and human subunits can accrue mutations via single-nucleotide polymorphisms in the parasite subunit. (D) Nonspecific activation of a human channel (e.g., via the action of ROS) cannot easily yield heritable changes in channel activity.

P: Site of phosphorylation; ROS: Reactive oxygen species; SH: A thiol that can be oxidized to a disulfide, presented as an example target of ROS generated by parasite oxidative stress.