Structural highlights
Function
[UBC12_HUMAN] Accepts the ubiquitin-like protein NEDD8 from the UBA3-NAE1 E1 complex and catalyzes its covalent attachment to other proteins. The specific interaction with the E3 ubiquitin ligase RBX1, but not RBX2, suggests that the RBX1-UBE2M complex neddylates specific target proteins, such as CUL1, CUL2, CUL3 and CUL4. Involved in cell proliferation.[1] [2]
Publication Abstract from PubMed
Little is known about molecular recognition of acetylated N termini, despite prevalence of this modification among eukaryotic cytosolic proteins. We report that the family of human DCN-like (DCNL) co-E3s, which promote ligation of the ubiquitin-like protein NEDD8 to cullin targets, recognizes acetylated N termini of the E2 enzymes UBC12 and UBE2F. Systematic biochemical and biophysical analyses reveal 40- and 10-fold variations in affinities among different DCNL-cullin and DCNL-E2 complexes, contributing to varying efficiencies of different NEDD8 ligation cascades. Structures of DCNL2 and DCNL3 complexes with N-terminally acetylated peptides from UBC12 and UBE2F illuminate a common mechanism by which DCNL proteins recognize N-terminally acetylated E2s and how selectivity for interactions dependent on N-acetyl-methionine are established through side chains recognizing distal residues. Distinct preferences of UBC12 and UBE2F peptides for inhibiting different DCNLs, including the oncogenic DCNL1 protein, suggest it may be possible to develop small molecules blocking specific N-acetyl-methionine-dependent protein interactions.
Structural Conservation of Distinctive N-terminal Acetylation-Dependent Interactions across a Family of Mammalian NEDD8 Ligation Enzymes.,Monda JK, Scott DC, Miller DJ, Lydeard J, King D, Harper JW, Bennett EJ, Schulman BA Structure. 2012 Nov 27. pii: S0969-2126(12)00409-1. doi:, 10.1016/j.str.2012.10.013. PMID:23201271[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gong L, Yeh ET. Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J Biol Chem. 1999 Apr 23;274(17):12036-42. PMID:10207026
- ↑ Huang DT, Miller DW, Mathew R, Cassell R, Holton JM, Roussel MF, Schulman BA. A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8. Nat Struct Mol Biol. 2004 Oct;11(10):927-35. Epub 2004 Sep 7. PMID:15361859 doi:10.1038/nsmb826
- ↑ Monda JK, Scott DC, Miller DJ, Lydeard J, King D, Harper JW, Bennett EJ, Schulman BA. Structural Conservation of Distinctive N-terminal Acetylation-Dependent Interactions across a Family of Mammalian NEDD8 Ligation Enzymes. Structure. 2012 Nov 27. pii: S0969-2126(12)00409-1. doi:, 10.1016/j.str.2012.10.013. PMID:23201271 doi:http://dx.doi.org/10.1016/j.str.2012.10.013
