Basic science for the clinician 40: ubiquitin, programmed protein degradation, and the proteasome.
mRNA is made from DNA. Protein is made from mRNA. Although one might say that "DNA is forever," the same cannot be said for mRNA or protein. These molecules are made in response to the cell's present needs; once the cell's circumstances change, a whole new repertoire of proteins may be needed and the previous set of proteins may be unnecessary, perhaps even deleterious. So, the cell must be able to eliminate the characters in the previous act in favor of the actors needed for the current act. In addition, there is good evidence that the DNA to mRNA to protein flow may not be efficient; abnormal proteins, as well as damaged or misfolded proteins, are quite common and must also be eliminated. This process depends on the ability of the cell to tag the protein to be eliminated with a small protein (or chain of these proteins) that targets the protein to a special structure for digestion into its constituent amino acids for recycling into new proteins. This very common protein tag was identified in the 1970s and called "ubiquitin"--it truly was everyplace! In addition, ubiquitin is crucial to targeting normal proteins to their appropriate place in or on the cell and for recycling of proteins. Ubiqutination of proteins and what follows this tagging are crucial to the normal function of cells. The complexity of these processes is being used for therapy in oncology now and perhaps in immunology and rheumatology in the near future.
Sigal
Leonard H
LH
Pharmaceutical Research Institute, Bristol-Myers Squibb, Pribceton, New Jersey 08543-4000, USA. leonard.sigal@bms.com
D001327:Autoimmune Diseases / Q000503:physiopathology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011489:Protein Denaturation / Q000502:physiology; D025801:Ubiquitin / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex