Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Abstract
The mTORC1 protein kinase complex plays central roles in regulating cell growth and metabolism and is implicated in common human diseases such as diabetes and cancer. The level of the amino acid leucine tells an organism a lot about its physiological state, including how much food is available, how much insulin is going to be needed, and whether new muscle mass can be made (see the Perspective by Buel and Blenis). Wolfson et al. identified a biochemical sensor of leucine, Sestrin2, which connects the concentration of leucine to the control of organismal metabolism and growth. When leucine bound to Sestrin2, it was released from a complex with the mTORC1 regulatory factor GATOR2, activating the mTORC1 complex. Saxton et al. describe the crystal structure of Sestrin2 and show how it specifically detects leucine. Aylett et al. determined the structure of human mTORC1 by cryoelectron microscopy and the crystal structure of a regulatory subunit, Raptor. The results reveal the structural basis for the function and intricate regulation of this important enzyme, which is also a strategic drug target.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2016
- Source ID
- 10.1126/science.aad2087
Entities
People
- David M. Sabatini
- Kevin E. Knockenhauer
- Lynne Chantranupong
- Michael E Pacold
- Rachel L. Wolfson
- Robert A. Saxton
- Thomas U. Schwartz
- Tim Wang
Organizations
- Argonne National Laboratory
- Broad Institute
- Damon Runyon Cancer Research Foundation
- Koch Institute for Integrative Cancer Research at MIT
- Massachusetts Institute of Technology
- National Institute of General Medical Sciences
- National Institutes of Health
- United States Department of Defense
- Whitehead Institute