Research ArticleStructural Biology

The apo-structure of the leucine sensor Sestrin2 is still elusive

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Science Signaling  20 Sep 2016:
Vol. 9, Issue 446, pp. ra92
DOI: 10.1126/scisignal.aah4497

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  • RE: Correction to PDB ID

    The authors wish to notify the readers that in Table 1 and in the Data and Materials Availability statement at the end of the full text, the PDB ID was incorrectly listed as 5T0P. The correct PDB ID is 5T0N. The full text and PDF have been updated to correct this typo.

    Competing Interests: None declared.
  • Sestrin2 and mTORC1 leucine sensing

    In a recently published review in Science Signaling, Lee, Cho, and Karin argued that Sestrin2 may not be the long-sought leucine sensor that communicates levels of this amino acid to the mTORC1 complex. Their arguments include (i) some genetic data that links Sestrins to AMPK activation, (ii) the citation of a paper that implicates the small GTPAse Rheb in complex with Rab1A as an activator of mTORC1 in the Golgi, particularly in colorectal cancer [Thomas et al., Cancer Cell 26, 754-769 (2014)] , in addition to the well-accepted control of mTORC1 by the Rag GTPase complex in lysosomes, and, perhaps most importantly, (iii) the presentation of a new ‘apo’ structure of Sestrin2 crystallized in the absence of exogenous leucine. This new structure displayed the identical protein conformation as the leucine-bound form previously solved by Schwartz, Sabatini, and colleagues. Lee, Cho, and Karin then argued that the lack of a conformational difference between the ‘apo’ and leucine-bound forms raised significant issues with how Sestrin2 could ‘sense’ leucine abundance. However, as Schawartz, Sabatini, and colleagues now report in this issue of Science Signaling, the ‘apo’ structure of Sestrin2 is not an apo- form at all, but instead contains something bound in the leucine-binding pocket, either leucine or likely malonate from the crystallization conditions. Regardless of the exact identity...

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    Competing Interests: None declared.

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