Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects
Year: 2014
Type: article
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddu611
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: University of Utah, Kreftforeningen, European Commission, Fonds Wetenschappelijk Onderzoek, Universitetet i Bergen, Norges Forskningsråd, Bergens Forskningsstiftelse, Vlaamse regering, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Center for Research Resources
Awards: VIRAL MRNA EXPORT MEDIATED BY THE HSV-1 ICP27 PROTEIN, G1897079340, Proteomics Research Infrastructure Maximising knowledge EXchange and access (XS), Structure and Function of Protein Acetyltransferases, Disease and immunity in marine brown algae, University of Utah Center for Clinical and Translational Science-UL1, G5432930453, G5704161608, Detailed analysis of the substrates and the specificity of the N-terminalacetyltransferases, G6222146311, G6275666395, Complementary use of ribosome profiling and positional proteomics for mapping the translation initiation and nascent protein modification landscape in human cell lines, G6747835480, G6878737446, G8514436827, Predoctoral Training at the Chemistry-Biology Interface, Consolidated Basic Cancer Research Program
OpenAlex ID: W2170236894