Saturday, August 27, 2011

The Many Functions of Ubiquitin

Ubiquitin (abbreviated as Ub) is described as a small, frequently-encountered molecule involved in the proteosomal degradation of proteins.  In reality, the addition of ubiquitin moieties to proteins can serve several functions and is now recognized as a common post-translational modification (PTM).

The classical ubiquitin pathway that first comes to mind is that of proteosomal degradation.  In this pathway, illustrated in the accompanying figure, ubiquitin is first "activated" by binding covalently to a cysteine residue on E1, the ubiquitin-activating enzyme, which requires the energy of ATP.  Then ubiquitin is transfered to a cysteine residue on E2, the ubiquitin-conjugating enzyme (no ATP is required here).  Finally, E2 binds to a scaffold called E3, the ubiquitin ligase, which also contains the target protein - illustrated in pink.  This target protein is then covalently linked to ubiquitin via a lysine residue.  Several rounds of this pathway then result in linear polyubiquitination of proteins, which is then recognized by other components in the cell that result in its recruitment to the proteasome and subsequent degradation (a topic of future posts).  The end result is that the target protein is broken down into small seven-to-eight amino acid pieces.

As mentioned above, there are three proteins involved in the attachment of ubiquitin to target proteins, E1, E2, and E3.  In the cell, E1s are the least plentiful (only one has been discovered thus far), while the human genome codes for tens of E2.  Several more E3 ligases have been discovered (and more every day).

Importantly, ubiquitination does not exclusively function in proteosome-mediated degradation of proteins.  Monoubiquitination, or the attachment of a single ubiquitin moiety to a protein, has been shown to have diverse effects on target proteins (see listbelow). Additionally, multiple monoubiquitination events can occur on a single protein, as can branched polyubiquitination.

Ubiquitin is not the sole small protein modifier.  Several molecules similar to ubiquitin have been described and exhibit diverse functions in cellular signaling (topics of future posts).  These proteins include SUMO (small ubiquitin-like modifier), NEDD, FATIO, and FUBI.  Needless to say, all of these proteins have some of the most adorable names in science.

The following list is a short compilation of ubiquitin functions, and, as we all know very well, no hard-and-fast rules exist for ubiquitin modifications (or science in general).
  • p53 ubiquitination by MDM2: cell cycle regulation, apoptosis
  • HIF1 ubiquitination by VHL: hypoxic response
  • Caspase 3 and 7 ubiquitination by XIAP: apoptosis
  • PCNA: DNA repair
  • RNA polymerase II: transcriptional regulation
  • H2AX and H2A: transcriptional regulation, protein recruitment
Of course, there are more proteins that are modified by ubiquitin, but I hope that the above table illustrates the diversity of the modification.

Interestingly, ubiquitin modifications are not forever: de-ubiquitinating enzymes (DUBs) remove ubiquitin moieties from tagged proteins.  Thus, the reversible ubiquination represents a dynamic cellular process.

Some cool (and important) papers and links:
Principles of ubiquitin and SUMO modifications in DNA repair
Non-traditional Functions of Ubiquitin and Ubiquitin-binding Proteins
The Ubiquitin System
Nonproteolytic Functions of Ubiquitin in Cell Signaling
Ubiquitin Function and Variety

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