Format

Send to

Choose Destination
Hum Mol Genet. 2015 Apr 1;24(7):1956-76. doi: 10.1093/hmg/ddu611. Epub 2014 Dec 8.

Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.

Author information

1
Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway.
2
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.
3
Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway.
4
Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY 11797, USA.
5
Department of Molecular Biology, University of Bergen, Bergen N-5020, Norway, Computational Biology Unit, Uni Computing, Uni Research AS, Bergen, Norway.
6
Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium, Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
7
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.
8
Caris Life Sciences, Phoenix, AZ, USA.
9
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.
10
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.
11
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.

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.

PMID:
25489052
PMCID:
PMC4355026
DOI:
10.1093/hmg/ddu611
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center