August 2006 Molecule of the Month by David Goodsell
Keywords: threonine-type endopeptidase activity, proteolysis involved in cellular protein catabolic process, HslUV protease complex, heat-shock proteins, proteosome, AAA+
How would you make a protein cutting machine that would be safe to use inside a cell? Digestive proteases like trypsin and pepsin are small and efficient?they diffuse up to proteins and start cutting. This would never work inside a cell. The cell needs to have more control, so that only obsolete or damaged proteins are destroyed. The AAA+ proteases are one solution to this problem. They use two tricks to ensure that only certain proteins are destroyed. First, they hide the protein destruction machinery inside a closed container, and second, they use a special protein pump to feed proteins into this destruction chamber.
Currently, the most complete structures of AAA+ proteases are for a bacterial protein called HslUV (short for Heat Shock Locus gene products U and V). One example is shown here, from PDB entry 1yyf. It is composed of two types of protein subunits. The protease subunits are arranged into a hollow barrel at the center, colored blue here. The active sites are hidden on the inside of the barrel. The AAA+ ATPase subunits, colored red and orange here, control the entry at either end of the complex. They form the pump that feeds proteins inside. HslUV is one of many heat shock proteins that are built when the cell heats up to dangerous levels. Heat can unfold proteins and cause unwanted aggregation, so a collection of heat shock chaperones and proteases are built to refold proteins into their proper form or dispose of heat-damaged proteins.
Our cells build a more complex version of HslUV: the proteosome. It has a larger destruction chamber at the center, composed of a stack of four ring-shaped protease complexes. At either end, there is a more complicated mechanism that looks for proteins attached to ubiquitin, and then uses a similar AAA+ ATPase to thread the protein into the chamber. For more information on this system, see the Molecule of the Month on ubiquitin.