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Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

(2018) SCIENCE. 362(6419). p.1177-1182
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Abstract
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 Lztrl haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.
Keywords
FAST INTERACTION REFINEMENT, RARE VARIANTS, MEMBRANE, FIREDOCK, REVEALS, CHARMM

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MLA
Steklov, M, S Pandolfi, MF Baietti, et al. “Mutations in LZTR1 Drive Human Disease by Dysregulating RAS Ubiquitination.” SCIENCE 362.6419 (2018): 1177–1182. Print.
APA
Steklov, M., Pandolfi, S., Baietti, M., Batiuk, A., Carai, P., Najm, P., Zhang, M., et al. (2018). Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. SCIENCE, 362(6419), 1177–1182.
Chicago author-date
Steklov, M, S Pandolfi, MF Baietti, A Batiuk, P Carai, P Najm, M Zhang, et al. 2018. “Mutations in LZTR1 Drive Human Disease by Dysregulating RAS Ubiquitination.” Science 362 (6419): 1177–1182.
Chicago author-date (all authors)
Steklov, M, S Pandolfi, MF Baietti, A Batiuk, P Carai, P Najm, M Zhang, H Jang, F Renzi, Y Cai, L Abbasi Asbagh, T Pastor, M De Troyer, M Simicek, E Radaelli, H Brems, E Legius, Jan Tavernier, Kris Gevaert, Francis Impens, L Messiaen, R Nussinov, S Heymans, Sven Eyckerman, and AA Sablina. 2018. “Mutations in LZTR1 Drive Human Disease by Dysregulating RAS Ubiquitination.” Science 362 (6419): 1177–1182.
Vancouver
1.
Steklov M, Pandolfi S, Baietti M, Batiuk A, Carai P, Najm P, et al. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. SCIENCE. 2018;362(6419):1177–82.
IEEE
[1]
M. Steklov et al., “Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination,” SCIENCE, vol. 362, no. 6419, pp. 1177–1182, 2018.
@article{8582698,
  abstract     = {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 Lztrl haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztrl abrogated Ras ubiquitination at lysine-170. LZTR-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.},
  author       = {Steklov, M and Pandolfi, S and Baietti, MF and Batiuk, A and Carai, P and Najm, P and Zhang, M and Jang, H and Renzi, F and Cai, Y and Abbasi Asbagh, L and Pastor, T and De Troyer, M and Simicek, M and Radaelli, E and Brems, H and Legius, E and Tavernier, Jan and Gevaert, Kris and Impens, Francis and Messiaen, L and Nussinov, R and Heymans, S and Eyckerman, Sven and Sablina, AA},
  issn         = {0036-8075},
  journal      = {SCIENCE},
  keywords     = {FAST INTERACTION REFINEMENT,RARE VARIANTS,MEMBRANE,FIREDOCK,REVEALS,CHARMM},
  language     = {eng},
  number       = {6419},
  pages        = {1177--1182},
  title        = {Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination},
  url          = {http://dx.doi.org/10.1126/science.aap7607},
  volume       = {362},
  year         = {2018},
}

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