期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11951-x
关键词
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资金
- Fondation pour le Recherche Medicale [DEQ2015031682]
- European Union [305608]
- Investments for the Future Program [ANR-10-IAHY-01]
- ANR KeoGamo [ANR-18-CE11-0008-01]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
- Dutch Kidney Foundation [15OP14]
- Fondation pour le Recherche Medicale (FRM)
- Agence Nationale de la Recherche (ANR) [ANR-18-CE11-0008] Funding Source: Agence Nationale de la Recherche (ANR)
N-6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t(6)A) is a universal modification essential for translational accuracy and efficiency. The t(6)A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
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