Healthcare (Commonwealth Union) – A group of Australian scientists from Monash University has uncovered the structure of a protein called ‘LYCHOS,’ which plays a key role in detecting and managing cell growth by monitoring cholesterol levels in the body.
Researchers of the study pointed out that cholesterol is essential for the healthy development of human cells, but the interaction between cells and cholesterol is a fragile balance. When this balance is disrupted, abnormal cell growth can occur, contributing to the development of cancers, neurological disorders, and other diseases.
In a study published in Nature, the Monash researchers used cryo-electron microscopy (cryo-EM) to map the 3D structure of LYCHOS for the first time. Their findings revealed that LYCHOS is a unique combination of a plant-like cell transporter, which is not typically found in humans, and a G protein-coupled receptor (GPCR).
The GPCR and plant-like transporter collaborate to sense cholesterol and control cell growth, making LYCHOS a promising new target for drug development to treat diseases driven by abnormal cell proliferation, such as cancer and neurological conditions.
Associate Professor Andrew Ellisdon, co-lead author and head of the Structural Biology of Signalling and Cancer lab at the Monash Biomedicine Discovery Institute (BDI), expressed the team’s excitement and surprise at their groundbreaking findings.
He pointed out that recent research has revealed that LYCHOS acts as a cholesterol sensor, helping regulate cell growth and metabolism by activating a protein complex known as mTORC1.
Associate Professor Ellisdon also indicated that despite this, the structure and function of LYCHOS have remained a mystery, limiting its potential as a drug target. To our surprise, our cryo-EM analysis has shown that human LYCHOS is a hybrid of a GPCR and a ‘PIN-FORMED’ (PIN) transporter—something typically found in plants and not previously believed to exist in humans.
He further indicated that just as plants orient their stems and leaves toward sunlight to optimize energy for photosynthesis, the plant-like transporter in LYCHOS allows human cells to detect when cholesterol levels are sufficient to trigger growth.
Associate Professor Michelle Halls, Head of the Spatial Organisation of Signalling Laboratory at the Monash Institute of Pharmaceutical Sciences (MIPS) and co-lead author, stated that the research opens up possibilities for developing new drugs.
Associate Professor Halls indicated that Cryo-electron microscopy (cryo-EM) has transformed drug discovery by allowing scientists to map the 3D structures of molecules that were previously too challenging to study. This cutting-edge technology has given us, along with drug developers worldwide, a detailed structural understanding of LYCHOS and its vital role as a cholesterol sensor and regulator.
“Furthermore, LYCHOS is an unusual example of a GPCR working as a smaller part of a large protein in a cell membrane. This finding expands what we know about GPCRs, showing that they can also be combined with other membrane proteins, like transporters, to create GPCR hybrids.”
“Together, the new structural information about LYCHOS opens up a whole new world for drugs designed to block abnormal cell growth and target things like tumour growth and spread, or impaired cholesterol metabolism resulting in neurological conditions,” added Associate Professor Halls.
Key contributors to the research team are the study’s lead authors, Dr. Charles Bayly-Jones and Dr. Chris Lupton, both from Monash BDI.
Dr. Bayly-Jones indicated that they are eager to keep investigating LYCHOS, a remarkable protein with significant potential to unlock new approaches for treating diseases driven by abnormal cell growth.
“As for the next steps, our focus will be to look at how we can develop a new class of cell growth inhibitors designed to block LYCHOS activity before it has the opportunity to drive disease,” said Dr Lupton.
The findings could play a key role for researchers who explore cancer cells behaviour and proteins associated with it.
