Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling

Science. 2017 Oct 20;358(6361):377-381. doi: 10.1126/science.aao1583. Epub 2017 Sep 21.

Abstract

The LAMTOR [late endosomal and lysosomal adaptor and MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) activator] complex, also known as "Ragulator," controls the activity of mTOR complex 1 (mTORC1) on the lysosome. The crystal structure of LAMTOR consists of two roadblock/LC7 domain-folded heterodimers wrapped and apparently held together by LAMTOR1, which assembles the complex on lysosomes. In addition, the Rag guanosine triphosphatases (GTPases) associated with the pentamer through their carboxyl-terminal domains, predefining the orientation for interaction with mTORC1. In vitro reconstitution and experiments with site-directed mutagenesis defined the physiological importance of LAMTOR1 in assembling the remaining components to ensure fidelity of mTORC1 signaling. Functional data validated the effect of two short LAMTOR1 amino acid regions in recruitment and stabilization of the Rag GTPases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry*
  • Carrier Proteins / ultrastructure
  • Crystallography, X-Ray
  • GTP Phosphohydrolases / chemistry
  • GTP Phosphohydrolases / ultrastructure
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / enzymology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Protein Domains
  • Signal Transduction

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • LAMTOR1 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • GTP Phosphohydrolases