In a significant breakthrough, scientists from Monash University have uncovered the structure of a previously elusive protein known as ‘LYCHOS.’ This discovery holds great promise in the fight against diseases driven by abnormal cell growth, such as cancer and neurological disorders, by shedding light on how human cells interact with cholesterol.
Cholesterol plays a crucial role in maintaining cell health and growth, but any imbalance in this delicate process can have serious consequences. Abnormal cell growth, triggered by cholesterol dysregulation, is often the underlying cause of many diseases. However, the Monash research team’s revelation about LYCHOS’ structure could pave the way for the development of new drugs aimed at tackling these health challenges.
For the first time, using cutting-edge cryo-electron microscopy (cryo-EM), the scientists have determined the three-dimensional structure of LYCHOS. This advanced technology allows researchers to view molecular structures at incredibly high resolutions, something that was previously impossible. The results, published in Nature, showed that LYCHOS is an unusual hybrid—partly resembling a plant transporter and partly a G protein-coupled receptor (GPCR). This unique structure enables LYCHOS to sense cholesterol levels and regulate cell growth, making it a potential target for new treatments for diseases linked to abnormal cell growth.
The findings were spearheaded by Associate Professor Andrew Ellisdon, leader of the Structural Biology of Signalling and Cancer lab at the Monash Biomedicine Discovery Institute (BDI), alongside Associate Professor Michelle Halls, head of the Spatial Organisation of Signalling Laboratory at the Monash Institute of Pharmaceutical Sciences (MIPS). Their joint work has opened the door to an entirely new class of treatments.
One of the key reasons LYCHOS is so exciting is its role in regulating cell growth through cholesterol detection. The protein essentially acts as a sensor, helping human cells decide when it’s time to grow, depending on the cholesterol levels in the body. If this mechanism goes wrong, it can lead to the uncontrolled growth that drives tumours and other diseases. This discovery of LYCHOS’ function could change the way researchers approach drug discovery for conditions triggered by cholesterol mismanagement.
Associate Professor Ellisdon, speaking on behalf of the team, expressed excitement over their findings, particularly the unexpected hybrid nature of LYCHOS. “It’s been recently discovered that LYCHOS acts as a cholesterol sensor and manages cell growth by activating a key protein complex called mTORC1,” he said. However, despite this knowledge, the exact structure and workings of LYCHOS had remained a mystery, which limited its potential as a target for drugs. The team’s cryo-EM research, to their surprise, revealed that LYCHOS is part GPCR and part ‘PIN-FORMED’ (PIN) transporter—a type of transporter generally only seen in plants.
The presence of this plant-like transporter in a human protein was entirely unexpected. GPCRs are already well-known targets for drug development, but finding one combined with a plant transporter in the human body is unprecedented. This discovery could help pharmaceutical researchers design drugs that are more precise in how they regulate cholesterol-related pathways in diseases.
In plants, PIN transporters are responsible for moving parts of the plant towards light in a process called phototropism. Similarly, the LYCHOS transporter works within human cells to detect cholesterol levels and manage cell growth. This analogy helps explain why understanding LYCHOS’ mechanism is so vital. If cholesterol levels are too low or too high, it triggers abnormal cell growth, which can lead to cancers or neurological conditions. By targeting LYCHOS, researchers could potentially control this growth before it spirals into disease.
The promise of LYCHOS as a drug target is further boosted by the revelations about its relationship to mTORC1, a key protein complex involved in regulating cell metabolism and growth. Since mTORC1 is implicated in numerous diseases, including cancers and metabolic disorders, being able to control its activation through LYCHOS opens up a wide range of therapeutic possibilities. Drugs could be developed to either inhibit or enhance LYCHOS’ activity depending on the specific needs of the patient’s condition.
For Associate Professor Michelle Halls, this discovery marks a new chapter in drug development, made possible by the advances in cryo-EM technology. She remarked that cryo-EM has revolutionised the field of structural biology by enabling scientists to view molecules previously too difficult to observe. This technique provides an exact structural description of LYCHOS, making it easier for drug discoverers to design molecules that interact with the protein in targeted ways.
What makes LYCHOS even more intriguing is its dual role as a GPCR, a class of proteins responsible for transmitting signals from outside the cell to the cell’s interior, and a transporter similar to those seen in plants. This is the first time scientists have observed a GPCR working as part of a larger protein in this way, expanding the understanding of how GPCRs can operate in the human body. GPCRs are the target of a significant portion of all drugs on the market today, and this discovery suggests that there could be many more GPCR-related opportunities yet to be explored.
The next steps for the Monash team involve digging deeper into LYCHOS and how its activity can be controlled or inhibited to prevent abnormal cell growth. Dr Charles Bayly-Jones and Dr Chris Lupton, key members of the research team, are already looking ahead to the potential applications of their work. They believe that targeting LYCHOS could offer a new way to stop diseases in their tracks by blocking the protein’s activity before it has a chance to fuel abnormal growth.
The possibilities unlocked by LYCHOS research have broad implications. Cancer therapies could become more effective and better tailored to individual patients. Neurological disorders linked to cholesterol metabolism, such as Alzheimer’s disease, may also benefit from treatments developed using this research. The newfound understanding of LYCHOS not only changes the landscape for drug discovery but also enriches the fundamental knowledge of how human cells interact with cholesterol, a molecule so essential yet potentially harmful when misregulated.
This breakthrough provides hope for a future where diseases driven by abnormal cell growth can be more effectively controlled. LYCHOS may be an unusual hybrid, but its potential as a therapeutic target is anything but ordinary.