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

Mariana E G de Araujo1, Andreas Naschberger2, Barbara G Fürnrohr2

  • 1Division of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Science (New York, N.Y.)
|September 23, 2017
PubMed

Insights

The LAMTOR complex, or Ragulator, regulates mTORC1 activity on lysosomes. LAMTOR1 is crucial for assembling the complex and stabilizing Rag GTPases, ensuring accurate mTORC1 signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The LAMTOR (late endosomal and lysosomal adaptor and MAPK and mTOR activator) complex, also known as Ragulator, is essential for regulating mechanistic target of rapamycin complex 1 (mTORC1) signaling.
  • mTORC1 activity is primarily controlled at the lysosome, and the LAMTOR complex acts as a key scaffold at this location.

Purpose of the Study:

  • To elucidate the structural organization of the LAMTOR complex.
  • To define the role of LAMTOR1 in the assembly and function of the Ragulator complex.
  • To understand the mechanism by which LAMTOR recruits and stabilizes Rag GTPases for mTORC1 activation.

Main Methods:

  • X-ray crystallography to determine the structure of the LAMTOR complex.
  • Site-directed mutagenesis to identify key amino acid regions in LAMTOR1.
  • In vitro reconstitution assays to study complex assembly and function.
  • Functional assays to validate the role of LAMTOR1 in GTPase binding and mTORC1 signaling.

Main Results:

  • The crystal structure reveals the LAMTOR complex is formed by two heterodimers stabilized by LAMTOR1, which anchors the complex to the lysosome.
  • Rag GTPases associate with the pentameric LAMTOR complex via their C-terminal domains, orienting them for mTORC1 interaction.
  • LAMTOR1 plays a critical role in the assembly of the entire complex and the recruitment/stabilization of Rag GTPases.

Conclusions:

  • LAMTOR1 is indispensable for the proper assembly of the Ragulator complex on lysosomes.
  • The structural and functional data highlight the importance of LAMTOR1 in ensuring the fidelity of lysosomal mTORC1 signaling by mediating Rag GTPase interactions.

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