4naw

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Template:STRUCTURE 4naw

Contents

Crystal Structure of Human ATG12~ATG5-ATG16N in complex with a fragment of ATG3

Template:ABSTRACT PUBMED 24191030

Disease

[A16L1_HUMAN] Crohn disease. Disease susceptibility is associated with variations affecting the gene represented in this entry.

Function

[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.[1] [2] [3] [4] [5] [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.[6] [7] [8] [9] [10] [11] [12] [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.[13] [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.[14] [15] [16] [17] [18] [19] 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.[20] [21] [22] [23] [24] [25]

About this Structure

4naw is a 16 chain structure with sequence from Human. Full crystallographic information is available from OCA.

Reference

  • 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
  1. ↑ Tanida I, Tanida-Miyake E, Komatsu M, Ueno T, Kominami E. Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p. J Biol Chem. 2002 Apr 19;277(16):13739-44. Epub 2002 Feb 1. PMID:11825910 doi:http://dx.doi.org/10.1074/jbc.M200385200
  2. ↑ 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
  3. ↑ Nemoto T, Tanida I, Tanida-Miyake E, Minematsu-Ikeguchi N, Yokota M, Ohsumi M, Ueno T, Kominami E. The mouse APG10 homologue, an E2-like enzyme for Apg12p conjugation, facilitates MAP-LC3 modification. J Biol Chem. 2003 Oct 10;278(41):39517-26. Epub 2003 Jul 30. PMID:12890687 doi:http://dx.doi.org/10.1074/jbc.C200334200
  4. ↑ Tanida I, Sou YS, Minematsu-Ikeguchi N, Ueno T, Kominami E. Atg8L/Apg8L is the fourth mammalian modifier of mammalian Atg8 conjugation mediated by human Atg4B, Atg7 and Atg3. FEBS J. 2006 Jun;273(11):2553-62. PMID:16704426 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05260.x
  5. ↑ Radoshevich L, Murrow L, Chen N, Fernandez E, Roy S, Fung C, Debnath J. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell. 2010 Aug 20;142(4):590-600. doi: 10.1016/j.cell.2010.07.018. PMID:20723759 doi:http://dx.doi.org/10.1016/j.cell.2010.07.018
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ Boada-Romero E, Letek M, Fleischer A, Pallauf K, Ramon-Barros C, Pimentel-Muinos FX. TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J. 2013 Feb 20;32(4):566-82. doi: 10.1038/emboj.2013.8. Epub 2013 Feb 1. PMID:23376921 doi:http://dx.doi.org/10.1038/emboj.2013.8
  14. ↑ Grand RJ, Milner AE, Mustoe T, Johnson GD, Owen D, Grant ML, Gregory CD. A novel protein expressed in mammalian cells undergoing apoptosis. Exp Cell Res. 1995 Jun;218(2):439-51. PMID:7796880 doi:http://dx.doi.org/S0014-4827(85)71177-9
  15. ↑ 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
  16. ↑ Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y, Jung YK. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem. 2005 May 27;280(21):20722-9. Epub 2005 Mar 18. PMID:15778222 doi:http://dx.doi.org/10.1074/jbc.M413934200
  17. ↑ 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
  18. ↑ Guevin C, Manna D, Belanger C, Konan KV, Mak P, Labonte P. Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology. 2010 Sep 15;405(1):1-7. doi: 10.1016/j.virol.2010.05.032. Epub 2010 Jun, 26. PMID:20580051 doi:http://dx.doi.org/10.1016/j.virol.2010.05.032
  19. ↑ Mai S, Muster B, Bereiter-Hahn J, Jendrach M. Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy. 2012 Jan;8(1):47-62. doi: 10.4161/auto.8.1.18174. Epub 2012 Jan 1. PMID:22170153 doi:http://dx.doi.org/10.4161/auto.8.1.18174
  20. ↑ Grand RJ, Milner AE, Mustoe T, Johnson GD, Owen D, Grant ML, Gregory CD. A novel protein expressed in mammalian cells undergoing apoptosis. Exp Cell Res. 1995 Jun;218(2):439-51. PMID:7796880 doi:http://dx.doi.org/S0014-4827(85)71177-9
  21. ↑ 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
  22. ↑ Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y, Jung YK. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem. 2005 May 27;280(21):20722-9. Epub 2005 Mar 18. PMID:15778222 doi:http://dx.doi.org/10.1074/jbc.M413934200
  23. ↑ 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
  24. ↑ Guevin C, Manna D, Belanger C, Konan KV, Mak P, Labonte P. Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection. Virology. 2010 Sep 15;405(1):1-7. doi: 10.1016/j.virol.2010.05.032. Epub 2010 Jun, 26. PMID:20580051 doi:http://dx.doi.org/10.1016/j.virol.2010.05.032
  25. ↑ Mai S, Muster B, Bereiter-Hahn J, Jendrach M. Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy. 2012 Jan;8(1):47-62. doi: 10.4161/auto.8.1.18174. Epub 2012 Jan 1. PMID:22170153 doi:http://dx.doi.org/10.4161/auto.8.1.18174

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