|
|
| Line 3: |
Line 3: |
| | <StructureSection load='3dbr' size='340' side='right'caption='[[3dbr]], [[Resolution|resolution]] 3.05Å' scene=''> | | <StructureSection load='3dbr' size='340' side='right'caption='[[3dbr]], [[Resolution|resolution]] 3.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3dbr]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DBR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3dbr]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DBR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.05Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1r4m|1r4m]], [[1r4n|1r4n]], [[1yov|1yov]], [[3dbh|3dbh]], [[3dbl|3dbl]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAE1, APPBP1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBA3, UBE1C ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NEDD8 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3dbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dbr OCA], [https://pdbe.org/3dbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dbr RCSB], [https://www.ebi.ac.uk/pdbsum/3dbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dbr ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3dbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dbr OCA], [https://pdbe.org/3dbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dbr RCSB], [https://www.ebi.ac.uk/pdbsum/3dbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dbr ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/ULA1_HUMAN ULA1_HUMAN]] Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation.<ref>PMID:10207026</ref> <ref>PMID:10722740</ref> <ref>PMID:12740388</ref> [[https://www.uniprot.org/uniprot/NEDD8_HUMAN NEDD8_HUMAN]] Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity, and thus promotes polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins.<ref>PMID:10318914</ref> <ref>PMID:10597293</ref> <ref>PMID:11953428</ref> [[https://www.uniprot.org/uniprot/UBA3_HUMAN UBA3_HUMAN]] Catalytic subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Down-regulates steroid receptor activity. Necessary for cell cycle progression.<ref>PMID:10207026</ref> <ref>PMID:9694792</ref> <ref>PMID:12740388</ref>
| + | [https://www.uniprot.org/uniprot/ULA1_HUMAN ULA1_HUMAN] Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation.<ref>PMID:10207026</ref> <ref>PMID:10722740</ref> <ref>PMID:12740388</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 38: |
Line 37: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Schulman, B A]] | + | [[Category: Schulman BA]] |
| - | [[Category: Souphron, J]] | + | [[Category: Souphron J]] |
| - | [[Category: Activating enzyme]]
| + | |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Ubl conjugation pathway]]
| + | |
| Structural highlights
Function
ULA1_HUMAN Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Post-translational covalent modification by ubiquitin and ubiquitin-like proteins (UBLs) is a major eukaryotic mechanism for regulating protein function. In general, each UBL has its own E1 that serves as the entry point for a cascade. The E1 first binds the UBL and catalyzes adenylation of the UBL's C-terminus, prior to promoting UBL transfer to a downstream E2. Ubiquitin's Arg 72, which corresponds to Ala72 in the UBL NEDD8, is a key E1 selectivity determinant: swapping ubiquitin and NEDD8 residue 72 identity was shown previously to swap their E1 specificity. Correspondingly, Arg190 in the UBA3 subunit of NEDD8's heterodimeric E1 (the APPBP1-UBA3 complex), which corresponds to a Gln in ubiquitin's E1 UBA1, is a key UBL selectivity determinant. Here, we dissect this specificity with biochemical and X-ray crystallographic analysis of APPBP1-UBA3-NEDD8 complexes in which NEDD8's residue 72 and UBA3's residue 190 are substituted with different combinations of Ala, Arg, or Gln. APPBP1-UBA3's preference for NEDD8's Ala72 appears to be indirect, due to proper positioning of UBA3's Arg190. By contrast, our data are consistent with direct positive interactions between ubiquitin's Arg72 and an E1's Gln. However, APPBP1-UBA3's failure to interact with a UBL having Arg72 is not due to a lack of this favorable interaction, but rather arises from UBA3's Arg190 acting as a negative gate. Thus, parallel residues from different UBL pathways can utilize distinct mechanisms to dictate interaction selectivity, and specificity can be amplified by barriers that prevent binding to components of different conjugation cascades.
Structural Dissection of a Gating Mechanism Preventing Misactivation of Ubiquitin by NEDD8's E1.,Souphron J, Waddell MB, Paydar A, Tokgoz-Gromley Z, Roussel MF, Schulman BA Biochemistry. 2008 Jul 25. PMID:18652489[4]
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
- ↑ Chen Y, McPhie DL, Hirschberg J, Neve RL. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem. 2000 Mar 24;275(12):8929-35. PMID:10722740
- ↑ Bohnsack RN, Haas AL. Conservation in the mechanism of Nedd8 activation by the human AppBp1-Uba3 heterodimer. J Biol Chem. 2003 Jul 18;278(29):26823-30. Epub 2003 May 10. PMID:12740388 doi:10.1074/jbc.M303177200
- ↑ Souphron J, Waddell MB, Paydar A, Tokgoz-Gromley Z, Roussel MF, Schulman BA. Structural Dissection of a Gating Mechanism Preventing Misactivation of Ubiquitin by NEDD8's E1. Biochemistry. 2008 Jul 25. PMID:18652489 doi:10.1021/bi800604c
|
