期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 7, 页码 1956-1976出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu611
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资金
- Stanley Institute for Cognitive Genomics
- Clinical Genetics Research Program: Phenotyping Core at the University of Utah (CCTS) [UL1RR025764]
- Research Foundation - Flanders (FWO-Vlaanderen) [G.0440.10, G.0269.13N]
- Research Council of Norway [197136, 230865]
- Norwegian Cancer Society [PR-2009-0222]
- Bergen Research Foundation (BFS)
- Western Norway Regional Health Authority
- National Institutes of Health [R01 GM020693]
- PRIME-XS - European Union [262067]
- University of Bergen
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.
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