Biochemistry Online: An Approach Based on Chemical Logic

CHAPTER 9 - SIGNAL TRANSDUCTION

D: mTOR and Nutrient Signaling

BIOCHEMISTRY - DR. JAKUBOWSKI

Last Update: 6/22/16

Learning Goals/Objectives for Chapter 9D:
After this reading, students will be able to

Describe the structure of mTOR Complex I and II;
Describe how rapamycin inhibits mTORC1;
Draw a cartoon of a generic protein kinase showing how its activity and specificity is regulated by activation and catalytic loops along with other protein binding partners;
Describe the structural differences between mTORC1 kinase and other kinases.
List typical substrates of mTORC1 and mTORC2;
Draw cartoons to show how Leu interacts with sestrin 2 and how this interaction activates mTORC1;
Describe how mTORC1 is recruited to lysosomal membranes and regulated by leucine through sestrin2, GATOR (GAP) proteins, Rag (small G) proteins, and Ragulator (GEF) proteins;
Explain how interactions of mTORC1 with Tsc 2/1 (GAP) proteins and Rheb (small G) proteins regulate mTORC1;
Describe how mTORC1 kinase activity is regulated by insulin through Akt and growth factors through MAP kinases;
Describe the different effects in metabolism mediated by AMPK and mTORC1;

D7. Links and References

Huang, J and Manning, B. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth Biochem J. 2008 Jun 1; 412(2): 179–190. doi: 10.1042/BJ20080281

Bar-Peled L1, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1Cell. 2012 Sep 14;150(6):1196-208. doi: 10.1016/j.cell.2012.07.032.

Wang, S. et al. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 09 Jan 2015: Vol. 347, Issue 6218, pp. 188-194 DOI: 10.1126/science.1257132

Buel, G and Blenis, J. mTORC1 specificity. Science 01 Jan 2016: Vol. 351, Issue 6268, pp. 25-26 DOI: 10.1126/science.aad9696

Aylett. C. et al 1. Architecture of human mTOR complex 1Science 01 Jan 2016: Vol. 351, Issue 6268, pp. 48-52 DOI: 10.1126/science.aaa3870

Haijuan Yang, Derek G. Rudge, Joseph D. Koos, Bhamini Vaidialingam, Hyo J. Yang & Nikola P. Pavletich. mTOR kinase structure, mechanism and regulation Nature 497, 217–223 (09 May 2013) doi:10.1038/nature12122

Alessi, D & Kulathu, Y. Structural biology: Security measures of a master regulator. Nature 497, 193–194 (09 May 2013) doi:10.1038/nature12101

Jing Li , Sang Gyun Kim , John Blenis. Rapamycin: One Drug, Many Effects. Cell Metabolism Volume 19, Issue 3, p373–379, 4 March 2014 DOI: http://dx.doi.org/10.1016/j.cmet.2014.01.001

Quinn, W and Birnbaum, M. Distinct mTORC1 pathways for transcription and cleavage of SREBP-1c PNAS | October 2, 2012 | vol. 109 | no. 40 www.pnas.org/cgi/doi/10.1073/pnas.1214113109

Buel G. and Blenis, J. Seeing mTORC1 specificity: Structural information reveals how a multiprotein complex responds to amino acid abundance

Aylett, C. et al. Architecture of human mTOR complex 1 JANUARY 2016 • VOL 351 ISSUE 6268 pg 48

Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway By Robert A. Saxton, Kevin E. Knockenhauer, Rachel L. Wolfson, Lynne Chantranupong, Michael E. Pacold, Tim Wang, Thomas U. Schwartz, David M. Sabatini Science01 Jan 2016 : 53-58

Wolfson, R. et al Sestrin2 is a leucine sensor for the mTORC1 pathway Science01 Jan 2016 : 43-48

Buel, G and Blenis, J. Seeing mTORC1 specificity. Science01 Jan 2016 : 25-26

Dibble, C and Manning. B. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. NATURE CELL BIOLOGY VOLUME 15 | NUMBER 6 | JUNE 2013 pg 555

Katiyar, S. et al. REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase. EMBO Rep. 2009 Aug; 10(8): 866–872. doi: 10.1038/embor.2009.93

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