2025-08-29_142812_nature_d41586-025-02694-5

A closer look at how cells sense dietary nutrients

URL: https://www.nature.com/articles/d41586-025-02694-5

Saved: 2025-08-29T21:28:17.358Z

RESEARCH BRIEFINGS 27 August 2025 A closer look at how cells sense dietary nutrients Cells need to sense the presence or absence of nutrients so that they can adjust their metabolism and growth accordingly. A key node in cellular nutrient sensing is the protein complex GATOR2. The mechanisms of how two nutrient-sensing proteins bind to and alter the configuration of GATOR2 have been determined. Twitter

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This is a summary of: Valenstein, M. L. et al. Structural basis for the dynamic regulation of mTORC1 by amino acids. Nature https://doi.org/10.1038/s41586-025-09428-7 (2025).

The mission

Cells must maintain a metabolic balance between nutrient supply and energy demand. When metabolic pressures shift, cells need to sense fluctuations in nutrient status and adjust their growth program accordingly. Specialized protein sensors detect individual nutrients in the cell and relay the nutrient status to the signalling nodes that control the ‘feed me’ signals for growth. When nutrient-signalling pathways are dysregulated, this balance is broken. As a result, the coordinated regulation of an organism’s homeostasis, health and survival depends partly on recognizing the presence or absence of nutrients and the associated signalling cues, because they affect the consumption and energy requirements for growth.

Understanding the drivers of this process, and how they work, could inform the development of therapies against diseases such as cancer and tuberous sclerosis, in which hyperactive ‘feed me’ signals enable aggressive disease progression.

The discovery

The mTORC1 protein complex responds to the presence of nutrients in the cell to coordinate cellular metabolism. Its ability to recognize these inputs relies on a set of coordinated signalling cascades that are orchestrated by another protein complex called GATOR21–3. To do this, GATOR2 must bind to nutrient-sensing proteins such as Sestrin2, which senses the amino acid leucine4, and CASTOR1, which senses another amino acid, called arginine5. However, we lack an understanding of how this regulation works on a molecular level, limiting our ability to modulate the pathway therapeutically.

We used a combination of approaches from cell and structural biology to identify how dietary nutrients are sensed in cells. GATOR2 has a drone-shaped body with dynamic ‘propellers’ protruding from an octagonal frame that binds to nutrient-sensing proteins. We discovered mechanisms by which Sestrin2 and CASTOR1 promote changes to the structural architecture of GATOR2, through a phenomenon called allostery, to convey information about the nutrient supply. Sestrin2 restricts the movement of one of the propellers of GATOR2 (a protein subunit called WDR24), limiting the ability of GATOR2 to relay signals to mTORC1 (Fig. 1). By contrast, CASTOR1 remodels the shape of the GATOR2 drone, squaring its frame and directly affecting its interactions with proteins that pass ‘feed me’ signals between GATOR2 and mTORC1. These mechanisms provide a tunable response for communicating the presence or absence of certain amino acids to mTORC1, by affecting the proportion of GATOR2 complexes that are inactivated by the nutrient sensors.

Figure 1 | Nutrient sensors change the dynamic WDR24 ‘propeller’ structure of the GATOR2 protein complex. Nutrient-sensing proteins such as CASTOR1 and Sestrin2 bind to the protein complex GATOR2, which has a key role in signalling the cell’s nutrient status. Left, the inactive ‘apo’ state of GATOR2, with its various protein subunits, is shaped like a drone with an octagonal frame and two WDR24 ‘propellers’. Middle, the binding of CASTOR1, which senses the amino acid arginine, squares the GATOR2 octagonal frame and causes one of the WDR24 propellers to attach to it. Right, Sestrin2, which senses the amino acid leucine, binds to the interface between the WDR24 propellers and the GATOR2 frame, keeping the GATOR2 complex locked in a double-propeller state.Credit: Valenstein, M. L. et al./Nature (CC BY-NC-ND 4.0)

The implications

This study provides a first view of a nutrient-sensing process that uses known sensors to regulate mTORC1 activation. These mechanistic insights show that stimulation of the mTORC1 pathway occurs with such rapid precision because the shape of GATOR2 is modulated by a tunable mechanism in response to fluctuations in nutrient supply.

We focused on sensing arginine and leucine, so we still lack information about the analogous mechanisms for other sensors, such as those that detect glucose or the amino acid methionine. The activation of mTORC1 also occurs more broadly as a response to the cumulative sufficiency of the nutrient supply, rather than to the supply of any single amino acid. We still do not know how the signals are integrated when multiple sensors bind to GATOR2 at the same time, and it is not clear how GATOR2 relays the integrated nutrient signal to mTORC1 to adjust the growth program.

Dysregulated mTORC1 function has been implicated in various disorders, including cancer, diabetes and some neurological diseases. However, drugs that act on mTORC1 are toxic, and cells can become resistant to such drugs through mutations that rewire metabolism. Our work establishes an initial blueprint for a therapeutic strategy to target this pathway. Moreover, given the large molecular frame of GATOR2, it is possible that it associates with other nutrient sensors that are yet to be discovered. There might even be tissue-specific sensors that provide site-specific modulation of mTORC1 activity. Targeting such sensors might be less toxic for treated individuals than broadly inhibiting the whole mTORC1 protein complex. — Karen Y. Linde-Garelli and Kacper B. Rogala are at Stanford University School of Medicine, Stanford, California, USA.

Expert opinion

The mTORC1 complex controls mammalian cell growth in response to nutrient availability and growth-factor signalling. The availability of different amino acids, sensed by Sestrin2 and CASTOR1, is transduced to mTORC1 through GATOR2. The authors decipher the interplay of Sestrin2 and CASTOR1 with GATOR2, using an elegant solution to overcome the previously observed compositional diversity of GATOR2 complexes. I particularly appreciate the authors’ careful reanalysis of, and comparison with, earlier structural data. — A reviewer

Behind the paper

Protein complexes are naturally dynamic, and larger assemblies can have more complex architecture and structural flexibility. GATOR2 contains 16 protein subunits that must assemble in the cell and flex dynamically to interact with nutrient sensors. To understand this mechanism, we needed to isolate GATOR2 from cells. However, when we first purified GATOR2, we found that only 1% of the protein particles were intact complexes, with the remaining 99% being disassembled. As a result, we could not distinguish between the protein’s natural motion and the motion induced by unwanted disassembly, limiting our ability to understand how GATOR2 works. To overcome this challenge, we engineered ‘single chain’ variants of GATOR2, in which we reduced the complexity from 16 subunits to 8 by linking individual subunits together. This eliminated the loss of subunits and enabled our analysis of the structural dynamics. — K.Y.L.-G. and K.B.R.

From the editor

This study reveals, at unprecedented resolution, how amino acid sensors regulate mTORC1 through GATOR2, resolving long-standing mechanistic questions in nutrient sensing. By combining structural biology with functional experiments, it uncovers a shared allosteric mechanism and provides a stabilized GATOR2 complex for future studies. Intriguingly, it not only advances fundamental understanding, but also identifies drug targets, making the work relevant for both basic science and therapeutic development. — Editorial team, Nature

doi: https://doi.org/10.1038/d41586-025-02694-5

‘Expert opinion’ is published under a CC BY 4.0 licence; Figure 1 is published under a CC BY-NC-ND 4.0 licence.

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