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| | ==Brag2 Sec7-PH (390-763)== | | ==Brag2 Sec7-PH (390-763)== |
| - | <StructureSection load='5nlv' size='340' side='right' caption='[[5nlv]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='5nlv' size='340' side='right'caption='[[5nlv]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nlv]] is a 1 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=5NLV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NLV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nlv]] is a 1 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=5NLV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NLV FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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]] 2.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IQSEC1, ARFGEP100, BRAG2, KIAA0763 ([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=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=5nlv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nlv OCA], [http://pdbe.org/5nlv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nlv RCSB], [http://www.ebi.ac.uk/pdbsum/5nlv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nlv 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=5nlv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nlv OCA], [https://pdbe.org/5nlv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nlv RCSB], [https://www.ebi.ac.uk/pdbsum/5nlv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nlv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IQEC1_HUMAN IQEC1_HUMAN]] In addition to accelerate GTP gamma S binding by ARFs of all three classes, it appears to function preferentially as a guanine nucleotide exchange protein for ARF6, mediating internalisation of beta-1 integrin.<ref>PMID:11226253</ref> <ref>PMID:16461286</ref> | + | [https://www.uniprot.org/uniprot/IQEC1_HUMAN IQEC1_HUMAN] In addition to accelerate GTP gamma S binding by ARFs of all three classes, it appears to function preferentially as a guanine nucleotide exchange protein for ARF6, mediating internalisation of beta-1 integrin.<ref>PMID:11226253</ref> <ref>PMID:16461286</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cherfils, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Nawrotek, A]] | + | [[Category: Cherfils J]] |
| - | [[Category: Hydrolase]] | + | [[Category: Nawrotek A]] |
| - | [[Category: Small gtpase]]
| + | |
| Structural highlights
Function
IQEC1_HUMAN In addition to accelerate GTP gamma S binding by ARFs of all three classes, it appears to function preferentially as a guanine nucleotide exchange protein for ARF6, mediating internalisation of beta-1 integrin.[1] [2]
Publication Abstract from PubMed
Lipidated small GTPases and their regulators need to bind to membranes to propagate actions in the cell, but an integrated understanding of how the lipid bilayer exerts its effect has remained elusive. Here we focused on ADP ribosylation factor (Arf) GTPases, which orchestrate a variety of regulatory functions in lipid and membrane trafficking, and their activation by the guanine-nucleotide exchange factor (GEF) Brag2, which controls integrin endocytosis and cell adhesion and is impaired in cancer and developmental diseases. Biochemical and structural data are available that showed the exceptional efficiency of Arf activation by Brag2 on membranes. We determined the high-resolution crystal structure of unbound Brag2 containing the GEF (Sec7) and membrane-binding (pleckstrin homology) domains, revealing that it has a constitutively active conformation. We used this structure to analyze the interaction of uncomplexed Brag2 and of the myristoylated Arf1/Brag2 complex with a phosphatidylinositol bisphosphate (PIP2) -containing lipid bilayer, using coarse-grained molecular dynamics. These simulations revealed that the system forms a close-packed, oriented interaction with the membrane, in which multiple PIP2 lipids bind the canonical lipid-binding site and unique peripheral sites of the PH domain, the Arf GTPase and, unexpectedly, the Sec7 domain. We cross-validated these predictions by reconstituting the binding and kinetics of Arf and Brag2 in artificial membranes. Our coarse-grained structural model thus suggests that the high efficiency of Brag2 requires interaction with multiple lipids and a well-defined orientation on the membrane, resulting in a local PIP2 enrichment, which has the potential to signal toward the Arf pathway.
Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane.,Karandur D, Nawrotek A, Kuriyan J, Cherfils J Proc Natl Acad Sci U S A. 2017 Sep 18. pii: 201707970. doi:, 10.1073/pnas.1707970114. PMID:28923919[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Someya A, Sata M, Takeda K, Pacheco-Rodriguez G, Ferrans VJ, Moss J, Vaughan M. ARF-GEP(100), a guanine nucleotide-exchange protein for ADP-ribosylation factor 6. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2413-8. PMID:11226253 doi:http://dx.doi.org/10.1073/pnas.051634798
- ↑ Dunphy JL, Moravec R, Ly K, Lasell TK, Melancon P, Casanova JE. The Arf6 GEF GEP100/BRAG2 regulates cell adhesion by controlling endocytosis of beta1 integrins. Curr Biol. 2006 Feb 7;16(3):315-20. PMID:16461286 doi:http://dx.doi.org/10.1016/j.cub.2005.12.032
- ↑ Karandur D, Nawrotek A, Kuriyan J, Cherfils J. Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane. Proc Natl Acad Sci U S A. 2017 Sep 18. pii: 201707970. doi:, 10.1073/pnas.1707970114. PMID:28923919 doi:http://dx.doi.org/10.1073/pnas.1707970114
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