The Molecular Architecture of Nutrient Sensing

From Fundamental Logic to Human Disease

For the last two decades, our Laboratory has focused on a single, fundamental question: How do cells perceive the presence of nutrients to make the decision to grow?

Our work has systematically reconstructed the signaling circuit connecting amino acid availability to the Target of Rapamycin Complex 1 (TORC1). By deciphering this molecular architecture in Saccharomyces cerevisiae, we established the foundational paradigm for how eukaryotic cells, from yeast to humans, translate nutritional cues into metabolic action.

We demonstrated that this system is not merely analogous between yeast and mammals, but evolutionarily conserved. The logic we defined provides the blueprint for understanding the mammalian Rag GTPase pathway and the etiology of Ragopathies, a class of human diseases caused by mutations in this exact machinery.

The Membrane-Bound Logic of Life

Our journey began with a genetic screen for mutants unable to exit rapamycin-induced growth arrest. This pivotal work from 2005 identified the EGO complex and provided the first clue that nutrient sensing is not a diffuse cytosolic event, but a spatially defined process occurring at a specific location: the vacuolar membrane.

We established that this complex functions as a dedicated, membrane-bound scaffold. We demonstrated that the subunit Ego1 utilizes N-terminal lipid modifications (myristoylation and palmitoylation) to firmly anchor the machinery to the vacuole (the yeast lysosome). This discovery introduced the concept of a "nutrient-sensing platform", a structural paradigm where a membrane anchor positions the signaling engines in the correct orientation to receive metabolic signals.

A Conserved Blueprint: From EGO to Ragulator

Building on this structural foundation, we characterized the Rag-family GTPases (Gtr1-Gtr2 in yeast) as the central processing unit of the pathway. We proposed and demonstrated that the nucleotide-loading state of these enzymes acts as the binary gatekeeper for TORC1 activity.

Crucially, the architecture we mapped in yeast proved to be the universal template for eukaryotic life. Structural studies revealed that the yeast EGO complex is the direct physical counterpart of the mammalian Ragulator. The "roadblock" folds we identified in Ego2 and Ego3 are structurally equivalent to the mammalian Lamtor proteins, serving the same function: gripping the GTPases and projecting their nucleotide-binding domains away from the membrane to capture TORC1.

We further resolved the regulatory logic of this switch by characterizing the SEA complex (orthologous to mammalian GATOR complex) and the Lst4-Lst7 complex (orthologous to FNIP-FLCN). By defining these opposing regulators, we completed the circuit, proving that a "dual-GTPase activating protein (GAP)" control logic is a fundamental, conserved feature of all eukaryotic cells.

• Implications for Human Health: The Ragopathies

  The map drawn in yeast has proved to possess direct predictive power for human health. The components characterized in our laboratory, from the membrane anchors to the GTPase switches, are the functional orthologs of human genes which, when mutated, lead to Ragopathies. These syndromes, characterized by epilepsy, cardiomyopathy, follicular lymphoma, and immune dysregulation, result from failures in the very machinery we have defined.

  Because the structural and functional logic is highly conserved, our work provides the mechanistic context necessary to understand these pathologies. We have effectively provided the "reference manual" for the molecular engines that fail in these human diseases.

• Outlook: The Spatiotemporal Dynamics of Life

  With the core "hardware" of nutrient sensing now defined, our focus shifts to the "software", the higher-order logic that governs cellular self-organization. We are moving beyond static pathway mapping toward a dynamic understanding of metabolic control. We propose that TORC1 is not a monolithic entity, but a self-organizing network of spatially distinct signaling hubs. Our current research investigates how these hubs are tuned to specific organelles and how they utilize molecular tethering to organize the cell in space and time.