The proteasome: structure and function
Some time ago the assumption had been made, that the cell is a stable unit. It was hard to believe that the tools of the cell, the proteins, which are synthesized at the expense of a lot of energy might be unstable and be degraded. In the meantime it has become clear that cells spend an enormous amount of energy to efficiently regulate their metabolism. Consequently also the degradation of proteins belongs to the regulatory repertoire of cells.
The lysosome (the vacuole in yeast) is a membrane surrounded intracellular organelle which contains a multitude of unspecific proteinases designed to degrade proteins into amino acids. Lysosome function is especially needed under stresses as is starvation to supply the cell with amino acid backbones for generation of energy and glucose. In contrast to the lysosome the second proteolytic device of the cell, the proteasome, has been recognized as an highly selective proteinase complex localized in the cytoplasm and the nucleus. In the research groups of Dr. Wolfgang Heinemeyer and Dr. Wolfgang Hilt structure and functions of this high molecular mass proteinase complex are investigated. It could be shown that the proteasome is composed of two complex components, the cylindric 20S core particle (20S proteasome) and a 19S cap particle which docks onto both ends of the 20S proteasome to yield the 26S proteasome. The 26S proteasome is viewed as the biologically active unit in the cell. The 20S core is composed of 28 subunits which consist of two different types, a and b. Seven different α- and seven different β-subunits build up homomeric rings which assemble to a heterodimeric cylinder complex of the type α7β7β7α7.
The enzyme contains three different catalytic activities, a chymotrypsin-like, a trypsin-like and a peptidyl glutamyl peptide hydrolysing activity. These three different activities are formed by three of the seven different β-subunits. In all three of these β-subunits an aminoterminal threonine is the catalytically active amino acid. Experimental and theoretical evidence point to the fact that proteins to be degraded are channeled through the opening of the 20S cylinder core in an unfolded form where they are cleaved by the two times three active sites into peptide pieces. It is thought that the 19S cap complex es responsible for recognition and - at least partly - for unfolding and "driving" the protein to be degraded through the cylinder. In most cases recognition of the proteins occurs via polyubiquitination. Here, the 76 amino acids containing protein is linked in a "tree"-like manner via a several component enzyme system (E1, E2, E3) onto the protein to be degraded.
It turned out that the 26S proteasome is essential for life. Its purpose is to selectively degrade a multitude of proteins upon specific signals. The respective degradation events are in many cases necessary for life. Proteins degraded upon specific signalling include metabolic enzymes, transcription factors, or proteins regulating the cell cycle as are cyclins, CDK-inhibitors and cell cycle regulators. Thus, the proteasome turns out to be a central switch within the cell. As such, and especially because of its involvement in cell cycle control the proteasome is viewed as a possible target for the therapy of certain diseases, e.g. cancer.
Contact:
Prof. Dr. Dieter H. Wolf
Phone: +49-(711)-685-4390; Fax: -4392
e-mail:
PD Dr. Wolfgang Heinemeyer
Phone: +49-(711)-685-4388; Fax: -4392
e-mail:
PD Dr. Wolfgang Hilt
Phone: +49-(711)-685-4388; Fax: -4392
e-mail:
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