Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination
作者： R. Nussinov , S. Heymans , S. Eyckerman , A. A. Sablina , M. Steklov
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摘要: The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss Schwann cells drives dedifferentiation and proliferation. By trapping complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate LZTR1-CUL3 complex. Ubiquitome analysis showed abrogated Ras ubiquitination at lysine-170. LZTR1-mediated inhibited signaling by attenuating association with membrane. Disease-associated mutations disrupted either complex formation or interaction proteins. regulation provides explanation role disease.
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Nelly Andrusier, Ruth Nussinov, Haim J. Wolfson, FireDock: fast interaction refinement in molecular docking. Proteins. ,vol. 69, pp. 139- 159 ,(2007) , 10.1002/PROT.21495
Taoling Zeng, Qun Wang, Jieying Fu, Qi Lin, Jing Bi, Weichao Ding, Yikai Qiao, Sheng Zhang, Wenxiu Zhao, Huayue Lin, Meilin Wang, Binfeng Lu, Xianming Deng, Dawang Zhou, Zhenyu Yin, Hong-Rui Wang, Impeded Nedd4-1-Mediated Ras Degradation Underlies Ras-Driven Tumorigenesis Cell Reports. ,vol. 7, pp. 871- 882 ,(2014) , 10.1016/J.CELREP.2014.03.045
M. J. Smith, B. Isidor, C. Beetz, S. G. Williams, S. S. Bhaskar, W. Richer, J. O'Sullivan, B. Anderson, S. B. Daly, J. E. Urquhart, A. Fryer, C. F. Rustad, S. J. Mills, A. Samii, D. du Plessis, D. Halliday, S. Barbarot, F. Bourdeaut, W. G. Newman, D. G. Evans, Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology. ,vol. 84, pp. 141- 147 ,(2015) , 10.1212/WNL.0000000000001129
Alexandre Arcaro, Stefano Volinia, Marketa J. Zvelebil, Rob Stein, Sandra J. Watton, Meredith J. Layton, Ivan Gout, Khatereh Ahmadi, Julian Downward, Michael D. Waterfield, Human phosphoinositide 3-kinase C2beta, the role of calcium and the C2 domain in enzyme activity. Journal of Biological Chemistry. ,vol. 273, pp. 33082- 33090 ,(1998) , 10.1074/JBC.273.49.33082
Arkadiusz Piotrowski, Jing Xie, Ying F Liu, Andrzej B Poplawski, Alicia R Gomes, Piotr Madanecki, Chuanhua Fu, Michael R Crowley, David K Crossman, Linlea Armstrong, Dusica Babovic-Vuksanovic, Amanda Bergner, Jaishri O Blakeley, Andrea L Blumenthal, Molly S Daniels, Howard Feit, Kathy Gardner, Stephanie Hurst, Christine Kobelka, Chung Lee, Rebecca Nagy, Katherine A Rauen, John M Slopis, Pim Suwannarat, Judith A Westman, Andrea Zanko, Bruce R Korf, Ludwine M Messiaen, None, Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas Nature Genetics. ,vol. 46, pp. 182- 187 ,(2014) , 10.1038/NG.2855
Emilia L Wu, Xi Cheng, Sunhwan Jo, Huan Rui, Kevin C Song, Eder M Dávila‐Contreras, Yifei Qi, Jumin Lee, Viviana Monje‐Galvan, Richard M Venable, Jeffery B Klauda, Wonpil Im, None, CHARMM-GUI Membrane Builder Toward Realistic Biological Membrane Simulations Journal of Computational Chemistry. ,vol. 35, pp. 1997- 2004 ,(2014) , 10.1002/JCC.23702
Toshiyuki Araki, M Golam Mohi, Fraz A Ismat, Roderick T Bronson, Ifor R Williams, Jeffery L Kutok, Wentian Yang, Lily I Pao, D Gary Gilliland, Jonathan A Epstein, Benjamin G Neel, Mouse model of Noonan syndrome reveals cell type– and gene dosage–dependent effects of Ptpn11 mutation Nature Medicine. ,vol. 10, pp. 849- 857 ,(2004) , 10.1038/NM1084
Pascal Genschik, Izabela Sumara, Esther Lechner, The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications The EMBO Journal. ,vol. 32, pp. 2307- 2320 ,(2013) , 10.1038/EMBOJ.2013.173
Lyuba Khavrutskii, Nadya I. Tarasova, Ruth Nussinov, Vadim Gaponenko, Hyunbum Jang, Sherwin J. Abraham, Tanmay S. Chavan, Ben Hitchinson, Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region. Journal of Biological Chemistry. ,vol. 290, pp. 9465- 9477 ,(2015) , 10.1074/JBC.M114.620724
Irene Paganini, Vivian Y Chang, Gabriele L Capone, Jeremie Vitte, Matteo Benelli, Lorenzo Barbetti, Roberta Sestini, Eva Trevisson, Theo JM Hulsebos, Marco Giovannini, Stanley F Nelson, Laura Papi, Expanding the mutational spectrum of LZTR1 in schwannomatosis European Journal of Human Genetics. ,vol. 23, pp. 963- 968 ,(2015) , 10.1038/EJHG.2014.220