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Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs

DOI: 10.1080/15548627.2019.1581009 DOI Help

Authors: Åsa Birna Birgisdottir (University of Tromsø – The Arctic University of Norway) , Stephane Mouilleron (The Francis Crick Institute) , Zambarlal Bhujabal (University of Tromsø – The Arctic University of Norway) , Martina Wirth (The Francis Crick Institute) , Eva Sjøttem (University of Tromsø – The Arctic University of Norway) , Gry Evjen (University of Tromsø – The Arctic University of Norway) , Wenxin Zhang (The Francis Crick Institute) , Rebecca Lee (The Francis Crick Institute (LIF)) , Nicola O’reilly (The Francis Crick Institute) , Sharon A. Tooze (The Francis Crick Institute) , Trond Lamark (University of Tromsø – The Arctic University of Norway) , Terje Johansen (University of Tromsø – The Arctic University of Norway)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Autophagy , VOL 21 , PAGES 1 - 23

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 9826 , 13775

Open Access Open Access

Abstract: 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.

Journal Keywords: Autophagy; ATG14; BECN1; GABARAP; LIR; PIK3C3

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Documents:
4r343453.txt.pdf