| Structural highlights
6gwj is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Gene: | LAGE3, DXS9879E, ESO3, ITBA2 (HUMAN), GON7, C14orf142 (HUMAN), OSGEP, GCPL1 (HUMAN) |
| Activity: | N(6)-L-threonylcarbamoyladenine synthase, with EC number 2.3.1.234 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[LAGE3_HUMAN] Galloway-Mowat syndrome. The disease is caused by mutations affecting the gene represented in this entry. [OSGEP_HUMAN] Galloway-Mowat syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
[LAGE3_HUMAN] Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. LAGE3 functions as a dimerization module for the complex.[1] [2] [OSGEP_HUMAN] Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. OSGEP likely plays a direct catalytic role in this reaction, but requires other protein(s) of the complex to fulfill this activity.[HAMAP-Rule:MF_03180][3] [4] [5] [6] [GON7_HUMAN] Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. GON7 likely plays a supporting role to the catalytic subunit OSGEP in the complex.[UniProtKB:P46984][7]
Publication Abstract from PubMed
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.
Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.,Arrondel C, Missoury S, Snoek R, Patat J, Menara G, Collinet B, Liger D, Durand D, Gribouval O, Boyer O, Buscara L, Martin G, Machuca E, Nevo F, Lescop E, Braun DA, Boschat AC, Sanquer S, Guerrera IC, Revy P, Parisot M, Masson C, Boddaert N, Charbit M, Decramer S, Novo R, Macher MA, Ranchin B, Bacchetta J, Laurent A, Collardeau-Frachon S, van Eerde AM, Hildebrandt F, Magen D, Antignac C, van Tilbeurgh H, Mollet G Nat Commun. 2019 Sep 3;10(1):3967. doi: 10.1038/s41467-019-11951-x. PMID:31481669[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Costessi A, Mahrour N, Sharma V, Stunnenberg R, Stoel MA, Tijchon E, Conaway JW, Conaway RC, Stunnenberg HG. The human EKC/KEOPS complex is recruited to Cullin2 ubiquitin ligases by the human tumour antigen PRAME. PLoS One. 2012;7(8):e42822. doi: 10.1371/journal.pone.0042822. Epub 2012 Aug 13. PMID:22912744 doi:http://dx.doi.org/10.1371/journal.pone.0042822
- ↑ Wan LC, Maisonneuve P, Szilard RK, Lambert JP, Ng TF, Manczyk N, Huang H, Laister R, Caudy AA, Gingras AC, Durocher D, Sicheri F. Proteomic analysis of the human KEOPS complex identifies C14ORF142 as a core subunit homologous to yeast Gon7. Nucleic Acids Res. 2017 Jan 25;45(2):805-817. doi: 10.1093/nar/gkw1181. Epub 2016, Nov 29. PMID:27903914 doi:http://dx.doi.org/10.1093/nar/gkw1181
- ↑ Edvardson S, Prunetti L, Arraf A, Haas D, Bacusmo JM, Hu JF, Ta-Shma A, Dedon PC, de Crecy-Lagard V, Elpeleg O. tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur J Hum Genet. 2017 May;25(5):545-551. doi: 10.1038/ejhg.2017.30. Epub 2017 Mar, 8. PMID:28272532 doi:http://dx.doi.org/10.1038/ejhg.2017.30
- ↑ Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, Gribouval O, Boyer O, Revy P, Jobst-Schwan T, Schmidt JM, Lawson JA, Schanze D, Ashraf S, Ullmann JFP, Hoogstraten CA, Boddaert N, Collinet B, Martin G, Liger D, Lovric S, Furlano M, Guerrera IC, Sanchez-Ferras O, Hu JF, Boschat AC, Sanquer S, Menten B, Vergult S, De Rocker N, Airik M, Hermle T, Shril S, Widmeier E, Gee HY, Choi WI, Sadowski CE, Pabst WL, Warejko JK, Daga A, Basta T, Matejas V, Scharmann K, Kienast SD, Behnam B, Beeson B, Begtrup A, Bruce M, Ch'ng GS, Lin SP, Chang JH, Chen CH, Cho MT, Gaffney PM, Gipson PE, Hsu CH, Kari JA, Ke YY, Kiraly-Borri C, Lai WM, Lemyre E, Littlejohn RO, Masri A, Moghtaderi M, Nakamura K, Ozaltin F, Praet M, Prasad C, Prytula A, Roeder ER, Rump P, Schnur RE, Shiihara T, Sinha MD, Soliman NA, Soulami K, Sweetser DA, Tsai WH, Tsai JD, Topaloglu R, Vester U, Viskochil DH, Vatanavicharn N, Waxler JL, Wierenga KJ, Wolf MTF, Wong SN, Leidel SA, Truglio G, Dedon PC, Poduri A, Mane S, Lifton RP, Bouchard M, Kannu P, Chitayat D, Magen D, Callewaert B, van Tilbeurgh H, Zenker M, Antignac C, Hildebrandt F. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet. 2017 Oct;49(10):1529-1538. doi: 10.1038/ng.3933. Epub 2017 Aug 14. PMID:28805828 doi:http://dx.doi.org/10.1038/ng.3933
- ↑ Costessi A, Mahrour N, Sharma V, Stunnenberg R, Stoel MA, Tijchon E, Conaway JW, Conaway RC, Stunnenberg HG. The human EKC/KEOPS complex is recruited to Cullin2 ubiquitin ligases by the human tumour antigen PRAME. PLoS One. 2012;7(8):e42822. doi: 10.1371/journal.pone.0042822. Epub 2012 Aug 13. PMID:22912744 doi:http://dx.doi.org/10.1371/journal.pone.0042822
- ↑ Wan LC, Maisonneuve P, Szilard RK, Lambert JP, Ng TF, Manczyk N, Huang H, Laister R, Caudy AA, Gingras AC, Durocher D, Sicheri F. Proteomic analysis of the human KEOPS complex identifies C14ORF142 as a core subunit homologous to yeast Gon7. Nucleic Acids Res. 2017 Jan 25;45(2):805-817. doi: 10.1093/nar/gkw1181. Epub 2016, Nov 29. PMID:27903914 doi:http://dx.doi.org/10.1093/nar/gkw1181
- ↑ Wan LC, Maisonneuve P, Szilard RK, Lambert JP, Ng TF, Manczyk N, Huang H, Laister R, Caudy AA, Gingras AC, Durocher D, Sicheri F. Proteomic analysis of the human KEOPS complex identifies C14ORF142 as a core subunit homologous to yeast Gon7. Nucleic Acids Res. 2017 Jan 25;45(2):805-817. doi: 10.1093/nar/gkw1181. Epub 2016, Nov 29. PMID:27903914 doi:http://dx.doi.org/10.1093/nar/gkw1181
- ↑ Arrondel C, Missoury S, Snoek R, Patat J, Menara G, Collinet B, Liger D, Durand D, Gribouval O, Boyer O, Buscara L, Martin G, Machuca E, Nevo F, Lescop E, Braun DA, Boschat AC, Sanquer S, Guerrera IC, Revy P, Parisot M, Masson C, Boddaert N, Charbit M, Decramer S, Novo R, Macher MA, Ranchin B, Bacchetta J, Laurent A, Collardeau-Frachon S, van Eerde AM, Hildebrandt F, Magen D, Antignac C, van Tilbeurgh H, Mollet G. Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. Nat Commun. 2019 Sep 3;10(1):3967. doi: 10.1038/s41467-019-11951-x. PMID:31481669 doi:http://dx.doi.org/10.1038/s41467-019-11951-x
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