title: Structure and evolution of N-domains in AAA metalloproteases.
abstract: Metalloproteases of the AAA (ATPases associated with various cellular activities) family play a crucial role in protein quality control within the cytoplasmic membrane of bacteria and the inner membrane of eukaryotic organelles. These membrane-anchored hexameric enzymes are composed of an N-terminal domain with one or two transmembrane helices, a central AAA ATPase module, and a C-terminal Zn(2+)-dependent protease. While the latter two domains have been well studied, so far, little is known about the N-terminal regions. Here, in an extensive bioinformatic and structural analysis, we identified three major, non-homologous groups of N-domains in AAA metalloproteases. By far, the largest one is the FtsH-like group of bacteria and eukaryotic organelles. The other two groups are specific to Yme1: one found in plants, fungi, and basal metazoans and the other one found exclusively in animals. Using NMR and crystallography, we determined the subunit structure and hexameric assembly of Escherichia coli FtsH-N, exhibiting an unusual α+β fold, and the conserved part of fungal Yme1-N from Saccharomyces cerevisiae, revealing a tetratricopeptide repeat fold. Our bioinformatic analysis showed that, uniquely among these proteins, the N-domain of Yme1 from the cnidarian Hydra vulgaris contains both the tetratricopeptide repeat region seen in basal metazoans and a region of homology to the N-domains of animals. Thus, it is a modern-day representative of an intermediate in the evolution of animal Yme1 from basal eukaryotic precursors.
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Franka
authors.initials: F
authors.lastname: Scharfenberg
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Serek-Heuberger
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Murray
authors.initials: M
authors.lastname: Coles
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Hartmann
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Habeck
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany. Electronic address: andrei.lupas@tuebingen.mpg.de.
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Lupas
authors.affiliation: Department of Protein Evolution, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors.forename: Vikram
authors.initials: V
authors.lastname: Alva
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000648:ultrastructure*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000648:ultrastructure*; D006829:Hydra / Q000201:enzymology; D008666:Metalloendopeptidases / Q000737:chemistry*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000648:ultrastructure*; D016415:Sequence Alignment
chemical_list: D029968:Escherichia coli Proteins; D029701:Saccharomyces cerevisiae Proteins; D049069:ATP-Dependent Proteases; C513383:FtsH protein, E coli; C082702:YME1 protein, S cerevisiae; D008666:Metalloendopeptidases; C114583:m-AAA proteases
keywords: AAA proteins; FtsH; Yme1; i-AAA; m-AAA