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1.A.91 The Plasmodial Surface Anion Channel (PSAC) Family

Erythrocytes infected with malaria parasites have increased permeability to ions and nutrients as mediated by the plasmodial surface anion channel (PSAC), recently linked to parasite Cytoadherence-linked asexual protein 3.2 (CLAG3.2) gene. Although the CLAG3.2-encoded protein is integral to the host membrane, its contribution to solute transport was unclear because it lacks conventional transmembrane domains and does not have homology to ion channel proteins in other organisms. Sharma et al. 2015 identified a probable CLAG3.2 transmembrane domain adjacent to a variant extracellular motif. Helical wheel analysis revealed strict segregation of polar and hydrophobic residues to opposite faces of a predicted α-helical transmembrane segment, suggesting that the domain lines a water-filled pore. A single CLAG3.2 mutation (A1210T) in a leupeptin-resistant PSAC mutant fell within this transmembrane domain and may affect pore structure. Allelic exchange transfection and site-directed mutagenesis revealed that this mutation alters solute selectivity in the channel. The A1210T mutation also reduces blocking affinity of PSAC inhibitors that bind at opposite channel faces, consistent with global changes in channel structure. Transfected parasites carrying this mutation survived leupeptin challenge significantly better than a transfection control. Thus, the A1210T mutation contributes directly to both altered PSAC activity and leupeptin resistance. These findings reveal the molecular basis of a novel antimalarial drug resistance mechanism, provide a framework for determining the channel's composition and structure, and should guide development of therapies targeting PSAC.

The generalized reaction catalyzed by the PSAC is: 

Solutes (out) ↔ Solutes (in).

References associated with 1.A.91 family:

Sharma P., Rayavara K., Ito D., Basore K. and Desai SA. (2015). A CLAG3 mutation in an amphipathic transmembrane domain alters malaria parasite nutrient channels and confers leupeptin resistance. Infect Immun. 83(6):2566-74. 25870226