Premium
Intrinsic lipid binding activity of ATG 16L1 supports efficient membrane anchoring and autophagy
Author(s) -
Dudley Leo J,
Cabodevilla Ainara G,
Makar Agata N,
Sztacho Martin,
Michelberger Tim,
Marsh Joseph A,
Houston Douglas R,
Martens Sascha,
Jiang Xuejun,
Gammoh Noor
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100554
Subject(s) - lipid anchored protein , autophagy , atg16l1 , autophagosome , microbiology and biotechnology , chemistry , biogenesis , membrane , biology , biochemistry , gene , apoptosis
Membrane targeting of autophagy‐related complexes is an important step that regulates their activities and prevents their aberrant engagement on non‐autophagic membranes. ATG 16L1 is a core autophagy protein implicated at distinct phases of autophagosome biogenesis. In this study, we dissected the recruitment of ATG 16L1 to the pre‐autophagosomal structure ( PAS ) and showed that it requires sequences within its coiled‐coil domain ( CCD ) dispensable for homodimerisation. Structural and mutational analyses identified conserved residues within the CCD of ATG 16L1 that mediate direct binding to phosphoinositides, including phosphatidylinositol 3‐phosphate ( PI 3P). Mutating putative lipid binding residues abrogated the localisation of ATG 16L1 to the PAS and inhibited LC 3 lipidation. On the other hand, enhancing lipid binding of ATG 16L1 by mutating negatively charged residues adjacent to the lipid binding motif also resulted in autophagy inhibition, suggesting that regulated recruitment of ATG 16L1 to the PAS is required for its autophagic activity. Overall, our findings indicate that ATG 16L1 harbours an intrinsic ability to bind lipids that plays an essential role during LC 3 lipidation and autophagosome maturation.