Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
Nat Commun. 2019 Sep 3;10(1):3967. doi: 10.1038/s41467-019-11951-x.
N-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (tA) is a universal modification essential for translational accuracy and efficiency. The tA 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.
N- threonyl - carbamoylation of adenosine 37 of ANN - type tRNAs ( tA ) is a universal modification essential for translational accuracy and efficiency. The tA 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.
N- threonyl - carbamoylation 于 adenosine 37 的 ANN - 型 tRNA （ tA ）是一种普遍的修饰，对翻译的准确性和效率至关重要。 tA 途径使用两种依次作用的酶，YRDC 和 OSGEP ，后者是多蛋白 KEOPS 复合物的一个亚基。我们最近在患有 Galloway - Mowat 综合征（ GAMOS ）的儿童中鉴定出五个 KEOPS 亚基中的四个基因编码的突变，GAMOS 是一种临床异质性常染色体隐性疾病，其特征是早期发病的类固醇耐药性肾病综合征和小头畸形。在这里，我们表明 YRDC 的突变导致 GAMOS 的一种极其严重的形式，而编码第五个 KEOPS 亚基的 GON7 的突变导致疾病的一种更温和的形式。 GON7 / LAGE3 / OSGEP 亚复合物的晶体结构表明，内在无序的 GON7 蛋白在与 LAGE3 结合时变得部分结构。 GON7 的结构和细胞特征表明其参与 KEOPS 复合物的细胞稳定性和四级排列。
