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| - | {{STRUCTURE_4mxp| PDB=4mxp | SCENE= }} | |
| - | ===Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM=== | |
| - | {{ABSTRACT_PUBMED_24530282}} | |
| | | | |
| - | ==Function== | + | ==Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM== |
| - | [[http://www.uniprot.org/uniprot/DRRA_LEGPH DRRA_LEGPH]] Virulence effector that plays a key role in hijacking the host vesicular trafficking by recruiting the small guanosine triphosphatase (GTPase) Rab1 to the cytosolic face of the Legionella-containing vacuole (LCVs). Acts as a GDP-GTP exchange factor (GEF) for the small GTPase Rab1 (RAB1A, RAB1B or RAB1C), thereby converting Rab1 to an active GTP-bound state, leading to the incorporation of Rab1 into LCVs. Also shows RabGDI displacement factor (GDF) activity; however, this probably represents a passive activity following the GEF activity. Also acts as an adenylyltransferase by mediating the addition of adenosine 5'-monophosphate (AMP) to 'Tyr-77' of host RAB1B, thereby rendering RAB1B constitutively active. Also has adenylyltransferase activity towards Rab6 and Rab35. Also displays guanylyltransferase activity by mediating the addition of guanosine 5'-monophosphate (GMP) to host RAB1B in vitro; however such activity remains uncertain in vivo. Specifically binds phosphatidylinositol 4-phosphate (PtdIns(4)P) lipids on the cytosolic surface of the phagosomal membrane shortly after infection.<ref>PMID:16824952</ref> <ref>PMID:17947549</ref> <ref>PMID:21822290</ref> <ref>PMID:20064470</ref> <ref>PMID:19942850</ref> <ref>PMID:20176951</ref> | + | <StructureSection load='4mxp' size='340' side='right'caption='[[4mxp]], [[Resolution|resolution]] 1.83Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[4mxp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Legionella_pneumophila_subsp._pneumophila_str._Philadelphia_1 Legionella pneumophila subsp. pneumophila str. Philadelphia 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MXP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MXP FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DB4:(2R)-3-{[(R)-HYDROXY{[(1R,2R,3R,4R,5S,6R)-2,3,5,6-TETRAHYDROXY-4-(PHOSPHONOOXY)CYCLOHEXYL]OXY}PHOSPHORYL]OXY}PROPANE-1,2-DIYL+DIBUTANOATE'>DB4</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=4mxp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mxp OCA], [https://pdbe.org/4mxp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mxp RCSB], [https://www.ebi.ac.uk/pdbsum/4mxp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mxp ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/DRRA_LEGPH DRRA_LEGPH] Virulence effector that plays a key role in hijacking the host vesicular trafficking by recruiting the small guanosine triphosphatase (GTPase) Rab1 to the cytosolic face of the Legionella-containing vacuole (LCVs). Acts as a GDP-GTP exchange factor (GEF) for the small GTPase Rab1 (RAB1A, RAB1B or RAB1C), thereby converting Rab1 to an active GTP-bound state, leading to the incorporation of Rab1 into LCVs. Also shows RabGDI displacement factor (GDF) activity; however, this probably represents a passive activity following the GEF activity. Also acts as an adenylyltransferase by mediating the addition of adenosine 5'-monophosphate (AMP) to 'Tyr-77' of host RAB1B, thereby rendering RAB1B constitutively active. Also has adenylyltransferase activity towards Rab6 and Rab35. Also displays guanylyltransferase activity by mediating the addition of guanosine 5'-monophosphate (GMP) to host RAB1B in vitro; however such activity remains uncertain in vivo. Specifically binds phosphatidylinositol 4-phosphate (PtdIns(4)P) lipids on the cytosolic surface of the phagosomal membrane shortly after infection.<ref>PMID:16824952</ref> <ref>PMID:17947549</ref> <ref>PMID:21822290</ref> <ref>PMID:20064470</ref> <ref>PMID:19942850</ref> <ref>PMID:20176951</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Recruitment of the Legionella pneumophila effector DrrA to the Legionella-containing vacuole, where it activates and AMPylates Rab1, is mediated by a P4M domain that binds phosphatidylinositol 4-phosphate [PI(4)P] with high affinity and specificity. Despite the importance of PI(4)P in Golgi trafficking and its manipulation by pathogens, the structural bases for PI(4)P-dependent membrane recruitment remain poorly defined. Here, we determined the crystal structure of a DrrA fragment including the P4M domain in complex with dibutyl PI(4)P and investigated the determinants of phosphoinositide recognition and membrane targeting. Headgroup recognition involves an elaborate network of direct and water-mediated interactions with basic and polar residues in the context of a deep, constrictive binding pocket. An adjacent hydrophobic helical element packs against the acyl chains and inserts robustly into PI(4)P-containing monolayers. The structural, biochemical, and biophysical data reported here support a detailed structural mechanism for PI(4)P-dependent membrane targeting by DrrA. |
| | | | |
| - | ==About this Structure==
| + | Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM.,Del Campo CM, Mishra AK, Wang YH, Roy CR, Janmey PA, Lambright DG Structure. 2014 Mar 4;22(3):397-408. doi: 10.1016/j.str.2013.12.018. Epub 2014, Feb 13. PMID:24530282<ref>PMID:24530282</ref> |
| - | [[4mxp]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MXP OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | <ref group="xtra">PMID:024530282</ref><references group="xtra"/><references/> | + | </div> |
| - | [[Category: Campo, C M.Del.]] | + | <div class="pdbe-citations 4mxp" style="background-color:#fffaf0;"></div> |
| - | [[Category: Janmey, P A.]] | + | == References == |
| - | [[Category: Lambright, D G.]]
| + | <references/> |
| - | [[Category: Mishra, A K.]] | + | __TOC__ |
| - | [[Category: Roy, C R.]] | + | </StructureSection> |
| - | [[Category: Wang, Y H.]] | + | [[Category: Large Structures]] |
| - | [[Category: Guanine nucleotide exchange factor]] | + | [[Category: Legionella pneumophila subsp. pneumophila str. Philadelphia 1]] |
| - | [[Category: Protein-lipid complex]] | + | [[Category: Del Campo CM]] |
| - | [[Category: Rab1 binding]] | + | [[Category: Janmey PA]] |
| | + | [[Category: Lambright DG]] |
| | + | [[Category: Mishra AK]] |
| | + | [[Category: Roy CR]] |
| | + | [[Category: Wang YH]] |
| Structural highlights
Function
DRRA_LEGPH Virulence effector that plays a key role in hijacking the host vesicular trafficking by recruiting the small guanosine triphosphatase (GTPase) Rab1 to the cytosolic face of the Legionella-containing vacuole (LCVs). Acts as a GDP-GTP exchange factor (GEF) for the small GTPase Rab1 (RAB1A, RAB1B or RAB1C), thereby converting Rab1 to an active GTP-bound state, leading to the incorporation of Rab1 into LCVs. Also shows RabGDI displacement factor (GDF) activity; however, this probably represents a passive activity following the GEF activity. Also acts as an adenylyltransferase by mediating the addition of adenosine 5'-monophosphate (AMP) to 'Tyr-77' of host RAB1B, thereby rendering RAB1B constitutively active. Also has adenylyltransferase activity towards Rab6 and Rab35. Also displays guanylyltransferase activity by mediating the addition of guanosine 5'-monophosphate (GMP) to host RAB1B in vitro; however such activity remains uncertain in vivo. Specifically binds phosphatidylinositol 4-phosphate (PtdIns(4)P) lipids on the cytosolic surface of the phagosomal membrane shortly after infection.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Recruitment of the Legionella pneumophila effector DrrA to the Legionella-containing vacuole, where it activates and AMPylates Rab1, is mediated by a P4M domain that binds phosphatidylinositol 4-phosphate [PI(4)P] with high affinity and specificity. Despite the importance of PI(4)P in Golgi trafficking and its manipulation by pathogens, the structural bases for PI(4)P-dependent membrane recruitment remain poorly defined. Here, we determined the crystal structure of a DrrA fragment including the P4M domain in complex with dibutyl PI(4)P and investigated the determinants of phosphoinositide recognition and membrane targeting. Headgroup recognition involves an elaborate network of direct and water-mediated interactions with basic and polar residues in the context of a deep, constrictive binding pocket. An adjacent hydrophobic helical element packs against the acyl chains and inserts robustly into PI(4)P-containing monolayers. The structural, biochemical, and biophysical data reported here support a detailed structural mechanism for PI(4)P-dependent membrane targeting by DrrA.
Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM.,Del Campo CM, Mishra AK, Wang YH, Roy CR, Janmey PA, Lambright DG Structure. 2014 Mar 4;22(3):397-408. doi: 10.1016/j.str.2013.12.018. Epub 2014, Feb 13. PMID:24530282[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Machner MP, Isberg RR. Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell. 2006 Jul;11(1):47-56. PMID:16824952 doi:10.1016/j.devcel.2006.05.013
- ↑ Machner MP, Isberg RR. A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science. 2007 Nov 9;318(5852):974-7. Epub 2007 Oct 18. PMID:17947549
- ↑ Mukherjee S, Liu X, Arasaki K, McDonough J, Galan JE, Roy CR. Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature. 2011 Aug 7;477(7362):103-6. doi: 10.1038/nature10335. PMID:21822290 doi:10.1038/nature10335
- ↑ Schoebel S, Oesterlin LK, Blankenfeldt W, Goody RS, Itzen A. RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity. Mol Cell. 2009 Dec 25;36(6):1060-72. PMID:20064470 doi:10.1016/j.molcel.2009.11.014
- ↑ Suh HY, Lee DW, Lee KH, Ku B, Choi SJ, Woo JS, Kim YG, Oh BH. Structural insights into the dual nucleotide exchange and GDI displacement activity of SidM/DrrA. EMBO J. 2010 Jan 20;29(2):496-504. Epub 2009 Nov 26. PMID:19942850 doi:10.1038/emboj.2009.347
- ↑ Zhu Y, Hu L, Zhou Y, Yao Q, Liu L, Shao F. Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA. Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4699-704. Epub 2010 Feb 22. PMID:20176951 doi:10.1073/pnas.0914231107
- ↑ Del Campo CM, Mishra AK, Wang YH, Roy CR, Janmey PA, Lambright DG. Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM. Structure. 2014 Mar 4;22(3):397-408. doi: 10.1016/j.str.2013.12.018. Epub 2014, Feb 13. PMID:24530282 doi:http://dx.doi.org/10.1016/j.str.2013.12.018
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