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| | ==Crystal Structure of Human ATG12~ATG5-ATG16N in complex with a fragment of ATG3== | | ==Crystal Structure of Human ATG12~ATG5-ATG16N in complex with a fragment of ATG3== |
| - | <StructureSection load='4naw' size='340' side='right' caption='[[4naw]], [[Resolution|resolution]] 2.19Å' scene=''> | + | <StructureSection load='4naw' size='340' side='right'caption='[[4naw]], [[Resolution|resolution]] 2.19Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4naw]] is a 16 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=4NAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NAW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4naw]] is a 16 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=4NAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NAW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gdk|4gdk]], [[4gdl|4gdl]]</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=4naw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4naw OCA], [https://pdbe.org/4naw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4naw RCSB], [https://www.ebi.ac.uk/pdbsum/4naw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4naw ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APG12, APG12L, ATG12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APG5L, ASP, ATG5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APG16L, ATG16L1, UNQ9393/PRO34307 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APG3, APG3L, ATG3 ([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=4naw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4naw OCA], [http://pdbe.org/4naw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4naw RCSB], [http://www.ebi.ac.uk/pdbsum/4naw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4naw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/A16L1_HUMAN A16L1_HUMAN]] Crohn disease. Disease susceptibility is associated with variations affecting the gene represented in this entry. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ATG3_HUMAN ATG3_HUMAN]] E2 conjugating enzyme required for the cytoplasm to vacuole transport (Cvt), autophagy, and mitochondrial homeostasis. Responsible for the E2-like covalent binding of phosphatidylethanolamine to the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A). The ATG12-ATG5 conjugate plays a role of an E3 and promotes the transfer of ATG8-like proteins from ATG3 to phosphatidylethanolamine (PE). This step is required for the membrane association of ATG8-like proteins. The formation of the ATG8-phosphatidylethanolamine conjugates is essential for autophagy and for the cytoplasm to vacuole transport (Cvt). Preferred substrate is MAP1LC3A. Also acts as an autocatalytic E2-like enzyme, catalyzing the conjugation of ATG12 to itself, ATG12 conjugation to ATG3 playing a role in mitochondrial homeostasis but not in autophagy. ATG7 (E1-like enzyme) facilitates this reaction by forming an E1-E2 complex with ATG3.<ref>PMID:11825910</ref> <ref>PMID:12207896</ref> <ref>PMID:12890687</ref> <ref>PMID:16704426</ref> <ref>PMID:20723759</ref> [[http://www.uniprot.org/uniprot/ATG12_HUMAN ATG12_HUMAN]] Ubiquitin-like protein involved in autophagy vesicles formation. Conjugation with ATG5 through an ubiquitin-like conjugating system involving also ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. The ATG12-ATG5 conjugate also regulates negatively the innate antiviral immune response by blocking the type I IFN production pathway through direct association with RARRES3 and MAVS. Plays also a role in translation or delivery of incoming viral RNA to the translation apparatus.<ref>PMID:12207896</ref> <ref>PMID:17709747</ref> <ref>PMID:19074260</ref> <ref>PMID:17999726</ref> <ref>PMID:19164948</ref> <ref>PMID:19666601</ref> <ref>PMID:23202584</ref> [[http://www.uniprot.org/uniprot/A16L1_HUMAN A16L1_HUMAN]] Plays an essential role in autophagy: interacts with ATG12-ATG5 to mediate the conjugation of phosphatidylethanolamine (PE) to LC3 (MAP1LC3A, MAP1LC3B or MAP1LC3C), to produce a membrane-bound activated form of LC3 named LC3-II.<ref>PMID:23376921</ref> [[http://www.uniprot.org/uniprot/ATG5_HUMAN ATG5_HUMAN]] Involved in autophagy vesicles formation. Conjugation with ATG12 through an ubiquitin-like conjugating system involving ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. Involved in mitochondrial quality control after oxidative damage, and in subsequent cellular longevity. The ATG12-ATG5 conjugate also regulates negatively the innate antiviral immune response by blocking the type I IFN production pathway through direct association with RARRES3 and MAVS. Plays also a role in translation or delivery of incoming viral RNA to the translation apparatus. HCV utilizes ATG5 as a proviral factor during the onset of viral infection. Plays a critical role in multiple aspects of lymphocyte development and is essential for both B and T lymphocyte survival and proliferation. Required for optimal processing and presentation of antigens for MHC II. Involved in the maintenance of axon morphology and membrane structures; as well as in normal adipocyte differentiation.<ref>PMID:7796880</ref> <ref>PMID:12207896</ref> <ref>PMID:15778222</ref> <ref>PMID:17709747</ref> <ref>PMID:20580051</ref> <ref>PMID:22170153</ref> May play an important role in the apoptotic process, possibly within the modified cytoskeleton. Its expression is a relatively late event in the apoptotic process, occurring downstream of caspase activity. Plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD.<ref>PMID:7796880</ref> <ref>PMID:12207896</ref> <ref>PMID:15778222</ref> <ref>PMID:17709747</ref> <ref>PMID:20580051</ref> <ref>PMID:22170153</ref> | + | [https://www.uniprot.org/uniprot/ATG12_HUMAN ATG12_HUMAN] Ubiquitin-like protein involved in autophagy vesicles formation. Conjugation with ATG5 through an ubiquitin-like conjugating system involving also ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. The ATG12-ATG5 conjugate also regulates negatively the innate antiviral immune response by blocking the type I IFN production pathway through direct association with RARRES3 and MAVS. Plays also a role in translation or delivery of incoming viral RNA to the translation apparatus.<ref>PMID:12207896</ref> <ref>PMID:17709747</ref> <ref>PMID:19074260</ref> <ref>PMID:17999726</ref> <ref>PMID:19164948</ref> <ref>PMID:19666601</ref> <ref>PMID:23202584</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4naw" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4naw" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Autophagy-related protein 3D structures|Autophagy-related protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Metlagel, Z]] | + | [[Category: Large Structures]] |
| - | [[Category: Otomo, C]] | + | [[Category: Metlagel Z]] |
| - | [[Category: Otomo, T]] | + | [[Category: Otomo C]] |
| - | [[Category: Takaesu, G]] | + | [[Category: Otomo T]] |
| - | [[Category: Autophagy]]
| + | [[Category: Takaesu G]] |
| - | [[Category: E3 ligase]]
| + | |
| - | [[Category: Protein transport-ligase complex]]
| + | |
| - | [[Category: Protein-protein conjugate]]
| + | |
| - | [[Category: Ubiquitin-like protein]]
| + | |
| Structural highlights
Function
ATG12_HUMAN Ubiquitin-like protein involved in autophagy vesicles formation. Conjugation with ATG5 through an ubiquitin-like conjugating system involving also ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. The ATG12-ATG5 conjugate also regulates negatively the innate antiviral immune response by blocking the type I IFN production pathway through direct association with RARRES3 and MAVS. Plays also a role in translation or delivery of incoming viral RNA to the translation apparatus.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The autophagic ubiquitin-like protein (ublp) autophagy-related (ATG)12 is a component of the ATG12 approximately ATG5-ATG16L1 E3 complex that promotes lipid conjugation of members of the LC3 ublp family. A role of ATG12 in the E3 complex is to recruit the E2 enzyme ATG3. Here we report the identification of the ATG12 binding sequence in the flexible region of human ATG3 and the crystal structure of the minimal E3 complexed with the identified binding fragment of ATG3. The structure shows that 13 residues of the ATG3 fragment form a short beta-strand followed by an alpha-helix on a surface area that is exclusive to ATG12. Mutational analyses of ATG3 confirm that four residues whose side chains make contacts with ATG12 are important for E3 interaction as well as LC3 lipidation. Conservation of these four critical residues is high in metazoan organisms and plants but lower in fungi. A structural comparison reveals that the ATG3 binding surface on ATG12 contains a hydrophobic pocket corresponding to the binding pocket of LC3 that accommodates the leucine of the LC3-interacting region motif. These findings establish the mechanism of ATG3 recruitment by ATG12 in higher eukaryotes and place ATG12 among the members of signaling ublps that bind liner sequences.
Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.,Metlagel Z, Otomo C, Takaesu G, Otomo T Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18844-9. doi:, 10.1073/pnas.1314755110. Epub 2013 Nov 4. PMID:24191030[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tanida I, Nishitani T, Nemoto T, Ueno T, Kominami E. Mammalian Apg12p, but not the Apg12p.Apg5p conjugate, facilitates LC3 processing. Biochem Biophys Res Commun. 2002 Sep 6;296(5):1164-70. PMID:12207896
- ↑ Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14050-5. Epub 2007 Aug 20. PMID:17709747 doi:http://dx.doi.org/10.1073/pnas.0704014104
- ↑ Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20567-74. doi:, 10.1073/pnas.0810611105. Epub 2008 Dec 12. PMID:19074260 doi:http://dx.doi.org/10.1073/pnas.0810611105
- ↑ Fader CM, Sanchez D, Furlan M, Colombo MI. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic. 2008 Feb;9(2):230-50. Epub 2007 Dec 7. PMID:17999726 doi:http://dx.doi.org/10.1111/j.1600-0854.2007.00677.x
- ↑ Terebiznik MR, Raju D, Vazquez CL, Torbricki K, Kulkarni R, Blanke SR, Yoshimori T, Colombo MI, Jones NL. Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy. 2009 Apr;5(3):370-9. Epub 2009 Apr 19. PMID:19164948
- ↑ Dreux M, Gastaminza P, Wieland SF, Chisari FV. The autophagy machinery is required to initiate hepatitis C virus replication. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14046-51. doi:, 10.1073/pnas.0907344106. Epub 2009 Aug 3. PMID:19666601 doi:http://dx.doi.org/10.1073/pnas.0907344106
- ↑ Otomo C, Metlagel Z, Takaesu G, Otomo T. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol. 2012 Dec 2. doi: 10.1038/nsmb.2431. PMID:23202584 doi:http://dx.doi.org/10.1038/nsmb.2431
- ↑ Metlagel Z, Otomo C, Takaesu G, Otomo T. Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18844-9. doi:, 10.1073/pnas.1314755110. Epub 2013 Nov 4. PMID:24191030 doi:http://dx.doi.org/10.1073/pnas.1314755110
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