Featured System - March 2009
Short description: The protozoan parasites that cause malaria multiply rapidly in the blood of infected individuals.
The protozoan parasites that cause malaria multiply rapidly in the blood of infected individuals. Each parasite invades a red blood cell, divides several times, and a few days later, several dozen new parasites burst out of the cell and into the bloodstream, ready to infect more cells. This destruction of red blood cells causes many of the life-threatening symptoms of malaria. As you might imagine, the destructive multiplication of these parasites requires a massive biosynthetic effort.
Malarial parasites must build a lot of membrane as they multiply, which requires a constant supply of fatty acids and glycerol, the building blocks of lipids. A recent study of the genome of the malaria parasite discovered an aquaglyceroporin, revealing that the parasite may get most of its glycerol directly from the host rather than building it itself using precursors from glycolysis. Glycerol is normally circulated through the bloodstream between adipose tissue, where fat is broken down, and the liver, which uses it for the construction of glucose to power the body. The malaria parasite uses a special channel protein, aquaglyceroporin, to steal this glycerol as it is being delivered.
Aquaglyceroporin is a passive channel, allowing glycerol and water to pass through the membrane from regions of higher concentration (outside the cell) to regions with lower concentration (inside the cell). It is a tetramer of identical subunits, arranged in a ring, with a channel running through the middle of each subunit. There is also a pore formed in the middle of the four subunits, but it is sealed by four tyrosines, which together form a watertight fireman's grip that blocks the channel.
Aquaglyceroporin is a member of a larger class of aquaporins that have the remarkable capability of allowing water and small molecules to pass through the membrane, while restricting the passage of protons and ions. This is essential, since the normal gradient of protons and ions across the cell membrane is essential for energy management and signaling. The remarkable specificity of aquaporins is accomplished through the use of a specificity filter. This is a ring of amino acids that recognize the molecules being passed, and exclude all others. In the malaria parasite aquaglyceroporin, this filter allows both water and glycerol to pass. Other aquaporins typically are more specific, and many organisms build separate channels for transport of water and for transport of glycerol-like molecules.
The recent structure of the malaria parasite aquaglyceroporin, solved by researchers at the PSI CSMP and available in PDB entry 3c02, gives a close-up look at how its dual specificity for glycerol and water is achieved. The filter includes an arginine that forms hydrogen bonds with glycerol and water, and two aromatic amino acids that cradle the hydrophobic face of glycerol. Typical water-specific aquaporins have a narrow channel, which is too small for glycerol to pass, and the arginine is tightly hydrogen-bonded to neighboring amino acids, reducing the energetic cost of desolvation. Typical glycerol-specific channels, on the other hand, have a wider channel to accommodate the larger glycerol molecule, and the arginine forms fewer hydrogen bonds with the surrounding protein, presumably increasing the energetic cost of desolvation and reducing the flow of water through the channel. The bifunctional aquaglyceroporin combines both of these traits: it has a wider channel that allows passage of glycerol, and a tightly hydrogen-bonded arginine to assist with water passage.
The JSmol tab below displays an interactive JSmol.
LeuT is composed of twelve alpha helices that cross back and forth across the cell membrane. Four helices that surround the binding site for leucine (yellow) and sodium (green) are highlighted here. Notice that two of them are kinked, wrapping around the sodium ions and forming a specific binding site for them. Imagine rocking these two helices back and forth to open alternately a path upwards and downwards. The antidepressant molecule (magenta) is bound on the side facing outside the cell. You
Newby ZER, O'Connell J, Robles-Colmenares Y, Khademi S, Miercke LJ and Stroud RM (2008) Crystal structure of the aquaglyceroporin PfAQP from the malarial parasite Plasmodium falciparum. Nature Structural & Molecular Biology 15, 619-625.
Hansen M, Kun JFJ, Schultz JE and Beitz E (2002) A single, bi-functional aquaglyceroporin in blood-stage Plasmodium falciparum malaria parasite. Journal of Biological Chemistry 277, 4874-4882.