6hol
From Proteopedia
Structure of ATG14 LIR motif bound to GABARAPL1
Structural highlights
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 PubMedAutophagosome 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
| ||||||||||||||||||
Categories: Bhujbal, Z | Birgisdottir, A B | Evjen, G | Johansen, T | Lamark, T | Lee, R | Mouilleron, S | Reilly, N O | Sjottem, E | Tooze, S | Wirth, M | Zhang, W | Atg8 | Autophagy | Lir | Signaling protein
