Proteopedia

6hol

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Structure of ATG14 LIR motif bound to GABARAPL1Structure of ATG14 LIR motif bound to GABARAPL1

Structural highlights

6hol is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:GABARAPL1, GEC1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GBRL1_HUMAN] Increases cell-surface expression of kappa-type opioid receptor through facilitating anterograde intracellular trafficking of the receptor. Involved in formation of autophagosomal vacuoles.[1] [2] [BAKOR_HUMAN] Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex PI3KC3-C1 (PubMed:18843052, PubMed:19050071). Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine (PubMed:19270696, PubMed:20713597). Promotes BECN1 translocation from the trans-Golgi network to autophagosomes (PubMed:20713597). Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1 (PubMed:23878393). Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK (PubMed:23878393). Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion (PubMed:25686604). Modulates the hepatic lipid metabolism (By similarity).[UniProtKB:Q8CDJ3][3] [4] [5] [6] [7] [8]

Publication Abstract from PubMed

Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation.

Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs.,Birgisdottir AB, Mouilleron S, Bhujabal Z, Wirth M, Sjottem E, Evjen G, Zhang W, Lee R, O'Reilly N, Tooze SA, Lamark T, Johansen T Autophagy. 2019 Feb 15. doi: 10.1080/15548627.2019.1581009. PMID:30767700[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Chen C, Li JG, Chen Y, Huang P, Wang Y, Liu-Chen LY. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. J Biol Chem. 2006 Mar 24;281(12):7983-93. Epub 2006 Jan 23. PMID:16431922 doi:M509805200
  2. ↑ Chakrama FZ, Seguin-Py S, Le Grand JN, Fraichard A, Delage-Mourroux R, Despouy G, Perez V, Jouvenot M, Boyer-Guittaut M. GABARAPL1 (GEC1) associates with autophagic vesicles. Autophagy. 2010 May;6(4):495-505. doi: 10.4161/auto.6.4.11819. Epub 2010 May 16. PMID:20404487 doi:10.4161/auto.6.4.11819
  3. ↑ Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell. 2008 Dec;19(12):5360-72. doi: 10.1091/mbc.e08-01-0080. Epub 2008, Oct 8. PMID:18843052 doi:http://dx.doi.org/10.1091/mbc.e08-01-0080
  4. ↑ Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19211-6. doi:, 10.1073/pnas.0810452105. Epub 2008 Dec 2. PMID:19050071 doi:http://dx.doi.org/10.1073/pnas.0810452105
  5. ↑ Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009 Apr;11(4):385-96. doi: 10.1038/ncb1846. Epub 2009 Mar 8. PMID:19270696 doi:http://dx.doi.org/10.1038/ncb1846
  6. ↑ Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis NT, Izumi T, Noda T, Yoshimori T. Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol. 2010 Aug 23;190(4):511-21. doi: 10.1083/jcb.200911141. Epub 2010 Aug, 16. PMID:20713597 doi:http://dx.doi.org/10.1083/jcb.200911141
  7. ↑ Fogel AI, Dlouhy BJ, Wang C, Ryu SW, Neutzner A, Hasson SA, Sideris DP, Abeliovich H, Youle RJ. Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. Mol Cell Biol. 2013 Sep;33(18):3675-88. doi: 10.1128/MCB.00079-13. Epub 2013 Jul , 22. PMID:23878393 doi:http://dx.doi.org/10.1128/MCB.00079-13
  8. ↑ Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz LM, Li J, Vivona S, Pfuetzner RA, Brunger AT, Zhong Q. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature. 2015 Feb 9. doi: 10.1038/nature14147. PMID:25686604 doi:http://dx.doi.org/10.1038/nature14147
  9. ↑ Birgisdottir AB, Mouilleron S, Bhujabal Z, Wirth M, Sjottem E, Evjen G, Zhang W, Lee R, O'Reilly N, Tooze SA, Lamark T, Johansen T. Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs. Autophagy. 2019 Feb 15. doi: 10.1080/15548627.2019.1581009. PMID:30767700 doi:http://dx.doi.org/10.1080/15548627.2019.1581009

6hol, resolution 1.40Å

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