Molecule of the Month: YES Complex

Bacteriophages are natural predators of bacteria. A bacteriophage binds to the surface of a bacterium and injects its genome, which is often composed of a single strand of DNA. This genome then directs the construction of many new copies of the bacteriophage, which burst out of the cell, killing it. Bacteriophages are everywhere in the environment, and most bacteria have many types of bacteriophages that attack them. For example, two well-studied bacteriophages, T4 and phiX174, both attack Escherichia coli bacteria.

Once bacteriophages have multiplied inside a cell, they face a challenge: how do they get out? Bacterial cells are often surrounded by a layer of peptidoglycan, a tough network of protein and sugar chains. So bacteriophages need proteins that corrupt this protective sheath. Bacteriophage T4 uses the enzyme lysozyme, which breaks the peptidoglycan chains. Bacteriophage phiX174, on the other hand, builds a small protein, termed protein E, that blocks the machinery that builds the peptidoglycan sheath.

PDB entry 8g02 reveals the mode of action of protein E. It binds to the bacterial enzyme MraY, which plays a central role in peptidoglycan synthesis. MraY attaches small precursors of peptidoglycan to a lipid carrier. The lipid makes it easy for other proteins to flip the precursor to the outside of the cell and attach it to growing peptidoglycan chains. Protein E blocks this process by binding to MraY and covering up the active site. Protein E also recruits a second protein, the chaperone protein SlyD, further occluding the active site of MraY. The whole complex, including MraY, protein E, and SlyD, has been termed the YES complex.

Since phages kill bacteria, they can be useful for treating infections. Phage therapy has been used for over a century, starting with treatment of dysentery with phages in 1919. It fell out of use in western medicine after the discovery of penicillin and other antibiotic drugs. Antibiotics have major advantages: they are easy to administer and they often target a wide range of bacteria. However, the recent emergence of antibiotic-resistant strains of bacteria has rekindled interest in phage therapy, which can provide an effective alternative for infections where no effective antibiotic drugs are available.

Bacterial cell walls also cause problems during the first steps of bacteriophage infection. Many bacteriophages, such as T4, have elaborate tails that bind to the surface of bacteria and inject their DNA through the wall. PhiX174 takes a simpler approach. It encodes a protein that assembles into a tube at the last minute, building a pathway through the cell wall just large enough for the DNA. PDB ID 4jpp includes the tube-forming portion of the protein.