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==Structure of a Glomulin-RBX1-CUL1 complex==
==Structure of a Glomulin-RBX1-CUL1 complex==
<StructureSection load='4f52' size='340' side='right' caption='[[4f52]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='4f52' size='340' side='right'caption='[[4f52]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4f52]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F52 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F52 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4f52]] is a 6 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=4F52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F52 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CUL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RBX1, RNF75, ROC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GLMN, FAP48, FAP68, VMGLOM ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4f52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f52 OCA], [http://pdbe.org/4f52 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f52 RCSB], [http://www.ebi.ac.uk/pdbsum/4f52 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f52 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=4f52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f52 OCA], [https://pdbe.org/4f52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f52 RCSB], [https://www.ebi.ac.uk/pdbsum/4f52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f52 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GLMN_HUMAN GLMN_HUMAN]] Glomuvenous malformation. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/CUL1_HUMAN CUL1_HUMAN]] Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110 (By similarity).<ref>PMID:9663463</ref> <ref>PMID:15531760</ref> <ref>PMID:15640526</ref> <ref>PMID:18644861</ref> <ref>PMID:19679664</ref>  [[http://www.uniprot.org/uniprot/GLMN_HUMAN GLMN_HUMAN]] Essential for normal development of the vasculature. May represent a naturally occurring ligand of the immunophilins FKBP59 and FKBP12. May function as an membrane anchoring protein. Isoform 1 may stimulate the p70S6K pathway. Isoform 2 may inhibit cell proliferation and increase IL2 production.<ref>PMID:11571281</ref> <ref>PMID:12604780</ref>  [[http://www.uniprot.org/uniprot/RBX1_HUMAN RBX1_HUMAN]] E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair. The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Through the RING-type zinc finger, seems to recruit the E2 ubiquitination enzyme, like CDC34, to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M.<ref>PMID:10579999</ref> <ref>PMID:11027288</ref> <ref>PMID:16751180</ref> <ref>PMID:16678110</ref> <ref>PMID:19679664</ref> 
[https://www.uniprot.org/uniprot/CUL1_HUMAN CUL1_HUMAN] Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110 (By similarity).<ref>PMID:9663463</ref> <ref>PMID:15531760</ref> <ref>PMID:15640526</ref> <ref>PMID:18644861</ref> <ref>PMID:19679664</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The approximately 300 human cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1's RING domain, regulates the RBX1-CUL1-containing SCF(FBW7) complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains the basis for GLMN's selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation, whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition.
 
Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface.,Duda DM, Olszewski JL, Tron AE, Hammel M, Lambert LJ, Waddell MB, Mittag T, Decaprio JA, Schulman BA Mol Cell. 2012 Aug 10;47(3):371-82. Epub 2012 Jun 28. PMID:22748924<ref>PMID:22748924</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4f52" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Cullin|Cullin]]
*[[Cullin 3D structures|Cullin 3D structures]]
*[[RING box protein|RING box protein]]
*[[RING box protein|RING box protein]]
*[[Ubiquitin protein ligase|Ubiquitin protein ligase]]
*[[Ring box protein 3D structures|Ring box protein 3D structures]]
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Duda, D M]]
[[Category: Large Structures]]
[[Category: Olszewski, J L]]
[[Category: Duda DM]]
[[Category: Schulman, B A]]
[[Category: Olszewski JL]]
[[Category: Cell cycle-ligase-signaling protein complex]]
[[Category: Schulman BA]]
[[Category: Cullin-ring e3 ligase]]
[[Category: Inhibitor]]

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