title: Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.
abstract: The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase (NAT) gene. The affected males harbor an Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural models and molecular dynamics simulations of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at the interface between Naa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex. N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a subset of NatA/NatE-type substrates as one etiology for Ogden syndrome. Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway. N-Terminal acetylation clearly plays a role in Ogden syndrome, thus revealing the in vivo importance of N-terminal acetylation in human physiology and disease.
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway.
authors.forename: Line M
authors.initials: LM
authors.lastname: Myklebust
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium, Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium, Thomas.Arnesen@mbi.uib.no Petra.vandamme@vib-ugent.be gholsonjlyon@gmail.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: Svein I
authors.initials: SI
authors.lastname: Støve
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY 11797, USA.
authors.forename: Max J
authors.initials: MJ
authors.lastname: Dörfel
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway.
authors.forename: Angèle
authors.initials: A
authors.lastname: Abboud
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Kalvik
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway.
authors.forename: Cedric
authors.initials: C
authors.lastname: Grauffel
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium, Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Jonckheere
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY 11797, USA, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Caris Life Sciences, Phoenix, AZ, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Swensen
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kaasa
authors.affiliation: Program in Gene Expression and Regulation, Wistar Institute, PA 19104, USA, Department of Chemistry, and Department of Biochemistry and Biophysics and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Glen
authors.initials: G
authors.lastname: Liszczak
authors.affiliation: Program in Gene Expression and Regulation, Wistar Institute, PA 19104, USA, Department of Chemistry, and Department of Biochemistry and Biophysics and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Reuter
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY 11797, USA, Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA, Thomas.Arnesen@mbi.uib.no Petra.vandamme@vib-ugent.be gholsonjlyon@gmail.com.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
authors.affiliation: Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium, Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway, Thomas.Arnesen@mbi.uib.no Petra.vandamme@vib-ugent.be gholsonjlyon@gmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011506:Proteins; D000123:Acetyltransferases