title: A conserved inter-domain communication mechanism regulates the ATPase activity of the AAA-protein Drg1.
abstract: AAA-ATPases fulfil essential roles in different cellular pathways and often act in form of hexameric complexes. Interaction with pathway-specific substrate and adaptor proteins recruits them to their targets and modulates their catalytic activity. This substrate dependent regulation of ATP hydrolysis in the AAA-domains is mediated by a non-catalytic N-terminal domain. The exact mechanisms that transmit the signal from the N-domain and coordinate the individual AAA-domains in the hexameric complex are still the topic of intensive research. Here, we present the characterization of a novel mutant variant of the eukaryotic AAA-ATPase Drg1 that shows dysregulation of ATPase activity and altered interaction with Rlp24, its substrate in ribosome biogenesis. This defective regulation is the consequence of amino acid exchanges at the interface between the regulatory N-domain and the adjacent D1 AAA-domain. The effects caused by these mutations strongly resemble those of pathological mutations of the AAA-ATPase p97 which cause the hereditary proteinopathy IBMPFD (inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia). Our results therefore suggest well conserved mechanisms of regulation between structurally, but not functionally related members of the AAA-family.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Prattes
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Loibl
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Zisser
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Luschnig
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kappel
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Rössler
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Grassegger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Altijana
authors.initials: A
authors.lastname: Hromic
authors.affiliation: CMBI 260, NCMLS, Radboud University Nijmegen Medical Centre P. O. Box 9101, 6500HB Nijmegen, The Netherlands.
authors.forename: Elmar
authors.initials: E
authors.lastname: Krieger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Gruber
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pertschy
authors.affiliation: Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Bergler
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000483:Alleles; D017124:Conserved Sequence; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D000072417:Protein Domains; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013489:Suppression, Genetic; D013696:Temperature
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases; C463962:AFG2 protein, S cerevisiae