For the first time, scientists have answered a longstanding question in cell biology about a partnership of proteins called the “KICSTOR–GATOR1 complex” which operate as a control system inside our cells, telling them when to grow and when to stop based on nutrient availability (especially amino acids).
The Monash University study, published in the prestigious journal Cell, used an ultra powerful imaging method called cryo-EM to reveal at near-atomic detail that KICSTOR positions GATOR1 so it can “switch off” cell growth when nutrients run low, helping the cell conserve resources.
The discovery provides a potentially transformative new window into understanding how our body’s cells control growth, respond to stress, and what might go wrong in diseases where this system breaks down, including cancers, metabolic disorders and neurodegenerative diseases.
Co-lead author of the study, Associate Professor Michelle Halls from the Monash Institute of Pharmaceutical Sciences (MIPS), said this pivotal scientific moment could help determine how to prevent the body’s cells from entering an unregulated growth mode.
“Cells need protein to grow, but when cells don’t properly strike the balance between growth and nutrient availability it can lead to uncontrolled cell growth or even total cell failure," Associate Professor Halls said.
“With many cancers for example, cells keep growing and dividing when they don’t have enough fuel, instead of slowing down like healthy cells would. Problems in the same nutrient-sensing brake can also make brain cells overly excitable and are now known to be a major genetic cause of certain childhood epilepsies.”
“By understanding how the KICSTOR-GATOR1 system helps cells sense when they can no longer support healthy growth, we can better understand what goes wrong in diseases where growth control is lost, such as cancer.”
Co-lead author of the study Professor Andrew Ellisdon, from the Monash Biomedicine Discovery Institute (BDI), said the findings fill a critical knowledge gap.
“The nutrient-sensing system built around the GATOR1 complex is ancient and conserved from yeast to humans, and in most animals it works together with a partner complex called KICSTOR. Its preservation across evolution highlights how essential it is for survival, but until now scientists have not been able to see how the two components physically connect to form the machinery that stops growth when internal protein levels fall,” Professor Ellisdon said.
“Because this nutrient-sensing brake sits at the heart of the cell’s decision to grow or conserve energy, it is tied to many aspects of human health. From ageing and metabolism to cancer, neurological disorders, muscle function, and immune responses.
“Understanding what KICSTOR–GATOR1 looks like gives researchers the structural foundation needed to explore how this system goes wrong in disease, and how it might be tuned to improve health.”
Next, the researchers will use their structural blueprint to study in more detail how the KICSTOR–GATOR1 complex is switched on and off, how it is altered in cancers and epilepsy, and whether its activity can be safely adjusted with new medicines to improve patient outcomes.
The full study titled Structure of the lysosomal KICSTOR–GATOR1–SAMTOR nutrient-sensing supercomplex can be found here.
DOI: 10.1016/j.cell.2025.12.005
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