View source for 3dbl


==Structural Dissection of a Gating Mechanism Preventing Misactivation of Ubiquitin by NEDD8's E1 (APPBP1-UBA3Arg190wt-NEDD8Ala72Gln)==
<StructureSection load='3dbl' size='340' side='right'caption='[[3dbl]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3dbl]] 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=3DBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DBL 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>
<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]], [[3dbr|3dbr]]</div></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=3dbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dbl OCA], [https://pdbe.org/3dbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dbl RCSB], [https://www.ebi.ac.uk/pdbsum/3dbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dbl ProSAT]</span></td></tr>
</table>
== 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>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/db/3dbl_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3dbl ConSurf].
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== 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<ref>PMID:18652489</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3dbl" style="background-color:#fffaf0;"></div>

==See Also==
*[[NEDD8|NEDD8]]
*[[3D structures of Ubiquitin activating enzyme|3D structures of Ubiquitin activating enzyme]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Schulman, B A]]
[[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]]