24.10.2024
LYCHOS: a novel human GPCR-transporter hybrid
LYCHOS (LYsosomal CHOlesterol Signalling) is an important human protein located in the lysosomal membrane and acting as a cholesterol sensor. LYCHOS transduces cholesterol levels into activation of mTORC1 signalling, thereby regulating cellular metabolism and growth. Despite its significance, the structural basis of how LYCHOS assembles and operates has remained elusive.
In a recent study published in Nature, researchers employed high-resolution cryo-EM to elucidate the structure of LYCHOS, revealing its unique assembly composed of a transporter-like domain fused to a GPCR domain. Both the GPCR and transporter domains work together to coordinate cholesterol sensing through a conserved cholesterol-binding motif located at the interface of these domains.
Surprisingly, the researchers found that the LYCHOS transporter-like domain is actually an orthologue of the plant PIN auxin transporter family, with a conserved crossover motif that enables a characteristic elevator-type conformational change. Analysis suggests a model in which the transporter domain’s elevator motion, similar to that observed in plant PIN transporters, facilitates cholesterol entry by repositioning blocking residues. Moreover, surface plasmon resonance analysis determined that LYCHOS retained the ability to bind indole-3-acetic acid (IAA), the main auxin produced by plants, although with a lower affinity compared to plant PINs. Consistent with this, solid-supported membrane (SSM)-based electrophysiology measurements of LYCHOS revealed that an order-of-magnitude higher concentration of IAA was required to elicit electrogenic currents equivalent to those initiated by PIN8 in plants. The authors concluded that these findings are consistent with anion binding but likely not with transport across the bilayer.
Importantly, mutations disrupting the cholesterol-binding mechanism significantly altered mTORC1 activity, underscoring the importance of LYCHOS in integrating cellular cholesterol levels with growth signalling pathways.
In conclusion, this study presents LYCHOS as an unusual example of a GPCR that functions as a component within a larger transmembrane assembly, also featuring a PIN-like transporter domain. This discovery classifies LYCHOS as a unique GPCR-transporter hybrid, potentially opening new avenues for modulating mTORC1 signalling in the treatment of diseases.
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Find the full article here: LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR
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