Function
Ubiquitin is a protein tag that targets cellular proteins for degradation. The degradation of cellular proteins is done through the 26S proteosome located in the nucleus and cytoplasm. [1] The body could have a variety of reasons for needing to degrade a protein including misfolding, old age, and replication errors. Ubiquitin has a major role in the maintenance of chromatin structure, gene expression, and the body’s stress response. The lysine residues function in a multitude of ways, but especially in the stress response involved in inflammatory signaling. The lysine63 residue engages the immune receptors where the RING E3 ligase TRAF6 builds lysine63 chains with the help of the E2 enzyme Ubc13-Uev1A to assemble the tags for signaling. Dimerization of the TRAF6 RING domain is crucial for the Ubiquitin chains to form properly. Ubiquitin is also important in endocytosis and kinase modification of substrates for cell monitoring. [2]
Disease
Ubiquitin is highly conserved in the evolutionary tree, but sometimes it can mutate. An abnormal form of Ubiquitin has been observed in Alzheimer’s patients and cleft palate patients. It has also been detected in patients with Down Syndrome. Each of these diseases or disorders is associated with a different alternative splicing mistake resulting in the multiple transcript variants seen. The chromosomes associated with the faulty Ubiquitin protein is on chromosomes 1, 2, 13, and 17. [3] More broadly, with a defective Ubiquitin protein, the inflammatory signaling and cell monitoring is not going to be at a prime. This would impact the body with inflammatory problems like allergies, asthma, and fevers.
Relevance
Ubiquitin is one of the most highly conserved proteins known at this time and so the relevance is very important for the cell to encode it properly. This protein is expressed throughout the body but mostly where lots of growth hormones occur most frequently. These places include liver, reproductive organs, kidney, brain & bone marrow. Being in places of growth and starting so low in the evolutionary tree suggests that Ubiquitin is crucial for homeostatic functions. Because it is so important for the cell, it is highly regulated with a half life between ten and twenty hours but usually closer to ten.[4]
Structural highlights
Ubiquitin has lots of lysine residues throughout the protein. The lysine residues play a large part in the binding ability of the protein due to its basic properties. It is made up of three domains with a total of 229 residues. The TRAF6 RING dimer forms a catalytic complex with RING interacting with the Ubiquitin conjugate and a zinc finger domain that opposes it in the Ubiquitin contact. The TRAF5 enables Ubiquitin to transfer from a TRAF6 bound conjugate. The TRAF RING domains can synthesize Ubiquitin chains for tagging the cellular proteins for degradation. [5]
Clicking on the link will show the active site lysines in space fill (CPK color)
