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| | ==The Crystal Structure of full length Arl3GppNHp in complex with UNC119a== | | ==The Crystal Structure of full length Arl3GppNHp in complex with UNC119a== |
| - | <StructureSection load='4goj' size='340' side='right' caption='[[4goj]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4goj' size='340' side='right'caption='[[4goj]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4goj]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GOJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GOJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4goj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GOJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GOJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gok|4gok]]</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=4goj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4goj OCA], [https://pdbe.org/4goj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4goj RCSB], [https://www.ebi.ac.uk/pdbsum/4goj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4goj ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Arl3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), UNC119, RG4 ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4goj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4goj OCA], [http://pdbe.org/4goj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4goj RCSB], [http://www.ebi.ac.uk/pdbsum/4goj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4goj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/U119A_HUMAN U119A_HUMAN]] Idiopathic CD4 lymphocytopenia;Cone rod dystrophy. Defects in UNC119 may be a cause of cone-rod dystrophy. A mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy: from 40 year old, the patient suffered from poor night vision, defective color vision and light-sensitivity. At 57 year old, she displayed reduced visual acuity, myopa, macular atrophy and pericentral ring scotomas. The disease was caused by a heterozygous mutation causing premature termination and truncated UNC119 protein with dominant-negative effect. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ARL3_MOUSE ARL3_MOUSE]] Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Required for normal cytokinesis and cilia signaling. Required for targeting proteins such as NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium (By similarity). Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms.<ref>PMID:15979089</ref> <ref>PMID:18376416</ref> [[http://www.uniprot.org/uniprot/U119A_HUMAN U119A_HUMAN]] Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Binds myristoylated NPHP3; however, in contrast to UNC119B, does not seem to play a major role in ciliary membrane localization of NPHP3. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells.<ref>PMID:22085962</ref> <ref>PMID:21642972</ref> | + | [https://www.uniprot.org/uniprot/ARL3_MOUSE ARL3_MOUSE] Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Required for normal cytokinesis and cilia signaling. Required for targeting proteins such as NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium (By similarity). Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms.<ref>PMID:15979089</ref> <ref>PMID:18376416</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: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Ismail, S]] | + | [[Category: Mus musculus]] |
| - | [[Category: Koerner, C]] | + | [[Category: Ismail S]] |
| - | [[Category: Miertzschke, M]] | + | [[Category: Koerner C]] |
| - | [[Category: Vetter, I]] | + | [[Category: Miertzschke M]] |
| - | [[Category: Wittinghofer, A]] | + | [[Category: Vetter I]] |
| - | [[Category: Xiang-Chen, Y]] | + | [[Category: Wittinghofer A]] |
| - | [[Category: Cilia]]
| + | [[Category: Xiang-Chen Y]] |
| - | [[Category: Gdi-like solubilizing factor]]
| + | |
| - | [[Category: Signaling protein]]
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| - | [[Category: Small g protein arl]]
| + | |
| Structural highlights
Function
ARL3_MOUSE Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). Required for normal cytokinesis and cilia signaling. Required for targeting proteins such as NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium (By similarity). Requires assistance from GTPase-activating proteins (GAPs) like RP2 and PDE6D, in order to cycle between inactive GDP-bound and active GTP-bound forms.[1] [2]
Publication Abstract from PubMed
Access to the ciliary membrane for trans-membrane or membrane-associated proteins is a regulated process. Previously, we have shown that the closely homologous small G proteins Arl2 and Arl3 allosterically regulate prenylated cargo release from PDEdelta. UNC119/HRG4 is responsible for ciliary delivery of myristoylated cargo. Here, we show that although Arl3 and Arl2 bind UNC119 with similar affinities, only Arl3 allosterically displaces cargo by accelerating its release by three orders of magnitude. Crystal structures of Arl3 and Arl2 in complex with UNC119a reveal the molecular basis of specificity. Contrary to previous structures of GTP-bound Arf subfamily proteins, the N-terminal amphipathic helix of Arl3.GppNHp is not displaced by the interswitch toggle but remains bound on the surface of the protein. Opposite to the mechanism of cargo release on PDEdelta, this induces a widening of the myristoyl binding pocket. This leads us to propose that ciliary targeting of myristoylated proteins is not only dependent on nucleotide status but also on the cellular localization of Arl3.
Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119.,Ismail SA, Chen YX, Miertzschke M, Vetter IR, Koerner C, Wittinghofer A EMBO J. 2012 Oct 17;31(20):4085-94. doi: 10.1038/emboj.2012.257. Epub 2012 Sep 7. PMID:22960633[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hanzal-Bayer M, Linari M, Wittinghofer A. Properties of the interaction of Arf-like protein 2 with PDEdelta. J Mol Biol. 2005 Jul 29;350(5):1074-82. PMID:15979089 doi:10.1016/j.jmb.2005.05.036
- ↑ Veltel S, Gasper R, Eisenacher E, Wittinghofer A. The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Nat Struct Mol Biol. 2008 Apr;15(4):373-80. Epub 2008 Mar 23. PMID:18376416 doi:nsmb.1396
- ↑ Ismail SA, Chen YX, Miertzschke M, Vetter IR, Koerner C, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 2012 Oct 17;31(20):4085-94. doi: 10.1038/emboj.2012.257. Epub 2012 Sep 7. PMID:22960633 doi:http://dx.doi.org/10.1038/emboj.2012.257
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