Ubc9 is a ubiquitin conjugating enzyme (E2) whose function involves transfer of ubiquitin or small ubiquitin-like modifier (SUMO) from ubiquitin activating enzyme (E1) to its designated substrate. Ubc9 is specifically involved in SUMO transfer[1].
Structure
Murine/human Ubc9 exhibits a single domain structure consisting of both alpha helices and beta-pleated sheets (PDB: 1U9A). Cys93 has been identified as the active residue and is located on a loop of amino acids (78-108) between beta sheet four and alpha helix two [1]. Crystal structure has shown that Ubc9 is the central protein in the SUMO-RanGAP1-Ubc9-Nup358 quaternary complex (PDB: 1Z5S), which forms in such a way as to enhance conjugation and transfer of the SUMO to its substrate [2]. Along with the formation of a thioester bond the its substrate, Ubc9 can also interact noncovelently with SUMO. Crystal structure of the noncovalent interaction between Ubc9 and SUMO1 (PDB: 2UYZ) have shown that the Ubc9 residues involved in this interaction are located at the end of helix one, on beta strand one, and along the following loop. These residues were shown to interact with the beta sheet of SUMO1 [3].
Function
Ubc9 is a part of the SUMOylation process. It is the enzyme responsible for ligating the SUMO to the protein. Depending on whether the reaction is done in vitro, it will ligate the SUMO directly to the substrate, and if done in vivo, the SUMO will be ligated to the conjugating enzyme and then put onto the substrate [2]. Initially, a thioester bond is formed between the SUMO and the E1 enzyme via an ATP-dependent reaction. The SUMO is then transferred to the active cystein of the E2, in this case, Ubc9. The SUMO is then ligated to a lysine side chain amino group of the substrate, during which an E3 enzyme may or may not be recruited. The use of E3 mediated transfer serves functions such as increasing substrate specificity [3]. Noncovalent interaction between Ubc9 and SUMO have been shown to be critical in the formation of SUMO chains, upon which in vivo functions such as protein degradation signaling are dependent. Mutagenesis studies on Ubc9 SUMO1 complex have shown that Ubc9H20D and SUMO1E67R mutation cause inhibition of noncovalent interaction between the two, and thus inhibit complex formation. A similar interaction is seen in the Ubc9-SUMO2 complex [3]. Lack of noncovalent interaction between Ubc9 and SUMO2 has been shown to inhibit SUMO2 chain formation [3].
Disease
Expression of Ubc9 has been found to be related to causing human diseases such as cancer, neurodegenerative diseases, and heart diseases. Studies have shown it to interact with tumor suppressor proteins such as p53, p63, and p73 and fundamental in the tumor progression and preventing apoptotic pathways. [3]
Relevance
Structural highlights
Anything in this section will appear adjacent to the 3D structure and will be scrollable.
- ↑ 1.0 1.1 Tong H, Hateboer G, Perrakis A, Bernards R, Sixma TK. Crystal structure of murine/human Ubc9 provides insight into the variability of the ubiquitin-conjugating system. J Biol Chem. 1997 Aug 22;272(34):21381-7. PMID:9261152
- ↑ Reverter D, Lima CD. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature. 2005 Jun 2;435(7042):687-92. PMID:15931224 doi:10.1038/nature03588
- ↑ 3.0 3.1 3.2 3.3 Knipscheer P, van Dijk WJ, Olsen JV, Mann M, Sixma TK. Noncovalent interaction between Ubc9 and SUMO promotes SUMO chain formation. EMBO J. 2007 Jun 6;26(11):2797-807. Epub 2007 May 10. PMID:17491593
