eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation.
eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation.
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DOI：
10.1016/j.molcel.2012.09.005
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发表时间：
2012-11-30
期刊：
影响因子：
16
通讯作者：
Basel-Vanagaite, Lina
中科院分区：
文献类型：
--
作者：
Borck, Guntram;Shin, Byung-Sik;Stiller, Barbara;Mimouni-Bloch, Aviva;Thiele, Holger;Kim, Joo-Ran;Thakur, Meghna;Skinner, Cindy;Aschenbach, Lara;Smirin-Yosef, Pola;Har-Zahav, Adi;Nuernberg, Gudrun;Altmueller, Janine;Frommolt, Peter;Hofmann, Kay;Konen, Osnat;Nuernberg, Peter;Munnich, Arnold;Schwartz, Charles E.;Gothelf, Doron;Colleaux, Laurence;Dever, Thomas E.;Kubisch, Christian;Basel-Vanagaite, Lina
翻译起始因子eIF2与GTP和启动物甲硫基trna形成三元复合物，结合40S核糖体，然后扫描mRNA选择AUG起始密码子进行蛋白质合成。在这里，我们发现以智力残疾和小头畸形为特征的人类x染色体神经系统疾病是由eIF2γ（由EIF2S3编码）的错义突变引起的，eIF2γ是异源三聚体eIF2复合物的核心亚基。对过表达eIF2γ突变体的人细胞和带有类似突变体的酵母eIF2γ细胞的生化研究发现，eIF2β亚基与eIF2γ的结合存在缺陷。与eIF2完整性缺失相一致的是，酵母eIF2γ的突变破坏了翻译起始密码子选择和eIF2在体内的功能，而这种功能被eIF2β的过表达所抑制。这些发现直接将智力残疾与翻译起始受损联系起来，并为eIF2功能部分丧失导致的人类疾病提供了机制基础。
Together with GTP and the initiator methionyl-tRNA, the translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the mutation in yeast eIF2γ impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpression of eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function.
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影响因子：
4.5
作者：
Takacs, Julie E.;Neary, Timothy B.;Lorsch, Jon R.
通讯作者：
Lorsch, Jon R.
影响因子：
64.8
作者：
Costa-Mattioli, M;Gobert, D;Sonenberg, N
通讯作者：
Sonenberg, N
影响因子：
64.5
作者：
Costa-Mattioli, Mauro;Gobert, Delphine;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
影响因子：
30.8
作者：
Tarpey, Patrick S.;Smith, Raffaella;Pleasance, Erin;Whibley, Annabel;Edkins, Sarah;Hardy, Claire;O'Meara, Sarah;Latimer, Calli;Dicks, Ed;Menzies, Andrew;Stephens, Phil;Blow, Matt;Greenman, Chris;Xue, Yali;Tyler-Smith, Chris;Thompson, Deborah;Gray, Kristian;Andrews, Jenny;Barthorpe, Syd;Buck, Gemma;Cole, Jennifer;Dunmore, Rebecca;Jones, David;Maddison, Mark;Mironenko, Tatiana;Turner, Rachel;Turrell, Kelly;Varian, Jennifer;West, Sofie;Widaa, Sara;Wray, Paul;Teague, Jon;Butler, Adam;Jenkinson, Andrew;Jia, Mingming;Richardson, David;Shepherd, Rebecca;Wooster, Richard;Tejada, M. Isabel;Martinez, Francisco;Carvill, Gemma;Goliath, Rene;de Brouwer, Arjan P. M.;van Bokhoven, Hans;Van Esch, Hilde;Chelly, Jamel;Raynaud, Martine;Ropers, Hans-Hilger;Abidi, Fatima E.;Srivastava, Anand K.;Cox, James;Luo, Ying;Mallya, Uma;Moon, Jenny;Parnau, Josef;Mohammed, Shehla;Tolmie, John L.;Shoubridge, Cheryl;Corbett, Mark;Gardner, Alison;Haan, Eric;Rujirabanjerd, Sinitdhorn;Shaw, Marie;Vandeleur, Lucianne;Fullston, Tod;Easton, Douglas F.;Boyle, Jackie;Partington, Michael;Hackett, Anna;Field, Michael;Skinner, Cindy;Stevenson, Roger E.;Bobrow, Martin;Turner, Gillian;Schwartz, Charles E.;Gecz, Jozef;Raymond, F. Lucy;Futreal, P. Andrew;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
4.1
作者：
Hashimoto, NN;Carnevalli, LS;Castilho, BA
通讯作者：
Castilho, BA