title: Atg18 function in autophagy is regulated by specific sites within its β-propeller.
abstract: Autophagy is a conserved degradative transport pathway. It is characterized by the formation of double-membrane autophagosomes at the phagophore assembly site (PAS). Atg18 is essential for autophagy but also for vacuole homeostasis and probably endosomal functions. This protein is basically a β-propeller, formed by seven WD40 repeats, that contains a conserved FRRG motif that binds to phosphoinositides and promotes Atg18 recruitment to the PAS, endosomes and vacuoles. However, it is unknown how Atg18 association with these organelles is regulated, as the phosphoinositides bound by this protein are present on the surface of all of them. We have investigated Atg18 recruitment to the PAS and found that Atg18 binds to Atg2 through a specific stretch of amino acids in the β-propeller on the opposite surface to the FRRG motif. As in the absence of the FRRG sequence, the inability of Atg18 to interact with Atg2 impairs its association with the PAS, causing an autophagy block. Our data provide a model whereby the Atg18 β-propeller provides organelle specificity by binding to two determinants on the target membrane.
authors.affiliation: Department of Cell Biology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
authors.forename: Ester
authors.initials: E
authors.lastname: Rieter
authors.forename: Fabian
authors.initials: F
authors.lastname: Vinke
authors.forename: Daniela
authors.initials: D
authors.lastname: Bakula
authors.forename: Eduardo
authors.initials: E
authors.lastname: Cebollero
authors.forename: Christian
authors.initials: C
authors.lastname: Ungermann
authors.forename: Tassula
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.forename: Fulvio
authors.initials: F
authors.lastname: Reggiori
mesh_terms: D000595:Amino Acid Sequence; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D001665:Binding Sites; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010588:Phagosomes / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C441008:ATG18 protein, S cerevisiae; C434064:ATG2 protein, S cerevisiae; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; C055525:phosphatidylinositol 3-phosphate