A team of scientists from Monash University has solved the structure of a protein known as 'LYCHOS', which can detect and regulate cell growth by sensing cholesterol levels in the body.
Human cells need cholesterol for healthy growth, but the way cells and cholesterol interact is a delicate balance. When cell growth becomes abnormal, it can quickly become a driving force behind many types of cancer, neurological disorders and other diseases.
Published in Nature, the Monash team used cryo‐electron microscopy (cryo‐EM) to, for the first time, determine the 3D structure of LYCHOS and have shown it is a unique hybrid of a cell transporter commonly found in plants (and not humans), and a G protein-coupled receptor (GPCR).
The GPCR and plant-like transporter work together to sense cholesterol and regulate cell growth, thus making LYCHOS an exciting new drug target for diseases perpetuated by abnormal cell growth which can lead to the formation of cancerous tumours and neurological dysfunction.
Co-lead author, Associate Professor Andrew Ellisdon who leads the Structural Biology of Signalling and Cancer lab at the Monash Biomedicine Discovery Institute (BDI), said the team was both excited and surprised by their discoveries.
"It's been recently discovered that LYCHOS functions as a cholesterol sensor and facilitates cell growth regulation and metabolism by activating a specific protein complex called mTORC1," Associate Professor Ellisdon said.
"However, the structure and mechanism of LYCHOS have remained unclear, hindering its potential as a drug target. To our great surprise, our cryo-EM studies have revealed that human LYCHOS is a hybrid of a GPCR and a 'PIN-FORMED' (PIN) transporter, typically associated with the plant kingdom and not previously thought to exist in humans."
"Much like the process whereby plants move their stems and leaves toward light to receive the maximum energy for photosynthesis, the LYCHOS plant-like transporter helps human cells sense when there's enough cholesterol to start growing."
Associate Professor Michelle Halls, Head of the Spatial Organisation of Signalling Laboratory at the Monash Institute of Pharmaceutical Sciences (MIPS) and co-lead author said the study paves the way for new drugs.
"Cryo-EM has revolutionised drug discovery by enabling researchers to determine the 3D structure of molecules previously too difficult to observe. This state-of-the-art technology has provided us, and drug discoverers around the world, with a precise structural description of the crucial role of LYCHOS as a cholesterol sensor and regulator," Associate Professor Halls said.
"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," Associate Professor Halls concluded.
Integral to the research team are the study's first authors, Dr Charles Bayly-Jones and Dr Chris Lupton, both from the Monash BDI.
"We're excited to continue exploring LYCHOS, which is a fascinating protein with a lot of potential to open up new avenues for the treatment of diseases triggered by abnormal cell growth," Dr Bayly-Jones said.
"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," concluded Dr Lupton.
Read the full paper published in Nature, titled LYCHOS (GPR155) is a human hybrid of a plant-like PIN transporter and GPCR.
DOI: https://doi.org/10.1038/s41586-024-08012-9
