title: Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy.
abstract: Reversible modification of Atg8 with phosphatidylethanolamine is crucial for autophagy, the bulk degradation system conserved in eukaryotic cells. Atg4 is a novel cysteine protease that processes and deconjugates Atg8. Herein, we report the crystal structure of human Atg4B (HsAtg4B) at 1.9-A resolution. Despite no obvious sequence homology with known proteases, the structure of HsAtg4B shows a classical papain-like fold. In addition to the papain fold region, HsAtg4B has a small alpha/beta-fold domain. This domain is thought to be the binding site for Atg8 homologs. The active site cleft of HsAtg4B is masked by a loop (residues 259-262), implying a conformational change upon substrate binding. The structure and in vitro mutational analyses provide the basis for the specificity and catalysis of HsAtg4B. This will enable the design of Atg4-specific inhibitors that block autophagy.
authors.affiliation: Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, N-12, W-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugawara
authors.forename: Nobuo N
authors.initials: NN
authors.lastname: Suzuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohsumi
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Inagaki
mesh_terms: D000595:Amino Acid Sequence; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D010206:Papain / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D013379:Substrate Specificity
chemical_list: D000071183:Autophagy-Related Proteins; D005982:Glutathione Transferase; C507524:ATG4B protein, human; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases; D010206:Papain