title: An intersubunit signaling network coordinates ATP hydrolysis by m-AAA proteases.
abstract: Ring-shaped AAA+ ATPases control a variety of cellular processes by substrate unfolding and remodeling of macromolecular structures. However, how ATP hydrolysis within AAA+ rings is regulated and coupled to mechanical work is poorly understood. Here we demonstrate coordinated ATP hydrolysis within m-AAA protease ring complexes, conserved AAA+ machines in the inner membrane of mitochondria. ATP binding to one AAA subunit inhibits ATP hydrolysis by the neighboring subunit, leading to coordinated rather than stochastic ATP hydrolysis within the AAA ring. Unbiased genetic screens define an intersubunit signaling pathway involving conserved AAA motifs and reveal an intimate coupling of ATPase activities to central AAA pore loops. Coordinated ATP hydrolysis between adjacent subunits is required for membrane dislocation of substrates, but not for substrate processing. These findings provide insight into how AAA+ proteins convert energy derived from ATP hydrolysis into mechanical work.
authors.affiliation: Institute for Genetics, Center for Molecular Medicine Cologne, University of Cologne, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Augustin
authors.forename: Florian
authors.initials: F
authors.lastname: Gerdes
authors.forename: Sukyeong
authors.initials: S
authors.lastname: Lee
authors.forename: Francis T F
authors.initials: FT
authors.lastname: Tsai
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.forename: Takashi
authors.initials: T
authors.lastname: Tatsuta
mesh_terms: D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D017124:Conserved Sequence; D004734:Energy Metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D021122:Protein Subunits; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015003:Yeasts / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development
chemical_list: D005656:Fungal Proteins; D021122:Protein Subunits; D000255:Adenosine Triphosphate; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; C114583:m-AAA proteases; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities