Ubiquitin
By
Jennifer McDowall
To view structure of ubiquitin
Ubiquitin, Prize Material
The Nobel Prize for Chemistry this year was awarded to three scientists who carried out pioneering research on ubiquitin, a eukaryotic protein that is so widespread from yeast to man that it gained its name as a derivation of the word “ubiquitous”. Aaron Ciechanover and Avram Hershko from the Israel Institute of Technology, and Irwin Rose from the University of California, pioneered research that unravelled the part ubiquitin plays in the degradation of proteins. Ubiquitin is now known to be involved in several other cellular processes as well, including quality control of nascent proteins, membrane trafficking, cell signalling, cell cycle control, X chromosome inactivation and the maintenance of chromosome structure, to name but a few. How can a tiny, 76-amino acid protein have so many varied roles? Ubiquitin (UB) acts through its attachment to other proteins (ubiquitinylation), and these protein modifications can alter the function or location of the protein, or target it for destruction. The C-terminus of UB extends as a 4-residue tail (Leu-Arg-Gly-Gly), where the terminal glycine residue can form an isopeptide bond with the amino group of a lysine side chain in a target protein. Alternatively, it can make an isopeptide bond with a lysine in another copy of UB to form a UB chain that ultimately attaches itself to a target protein. In general, the number and placement of UB molecules added to a protein helps to determine its future: a single copy of UB acts to modify a protein’s function, while multiple copies of UB will either modify a protein’s function or target it for degradation by the 26S proteasome, depending upon the position of the UB subunits.
Cunningly, several pathogenic bacteria have developed the ability to tap into eukaryotic UB-mediated processes to manipulate their hosts. In particular, the host immune response can be suppressed through the inhibition of the NFkB signalling system. The transcription factor NFkB is responsible for activating genes involved in the immune response, but is inhibited by its association with the inhibitor IkB. The immune response is triggered by the ubiquitinylation of IkB to target it for degradation, which releases NFkB so it can enter the nucleus and transcribe genes required to mount an immune reaction. Certain bacteria are able to interfere with this system by either preventing the ubiquitinylation of IkB (as is found with non-pathogenic enteric bacteria that form part of the intestinal microflora), or by cleaving ubiquitin from IkB (as with the ubiquitin-like cysteine proteases found in several animal and plant pathogens) – either way, IkB evades degradation and suppresses the immune response by inhibiting NFkB.