8U54
The mTORC1 cholesterol sensor LYCHOS (GPR155)
Summary for 8U54
| Entry DOI | 10.2210/pdb8u54/pdb |
| EMDB information | 41912 |
| Descriptor | Integral membrane protein GPR155, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total) |
| Functional Keywords | pin-formed, gpcr, cholesterol, auxin, transporter, cell-growth, mtorc1, cancer, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 198996.20 |
| Authors | Bayly-Jones, C.,Lupton, C.J.,Ellisdon, A.M. (deposition date: 2023-09-12, release date: 2024-09-18, Last modification date: 2024-11-13) |
| Primary citation | Bayly-Jones, C.,Lupton, C.J.,Keen, A.C.,Dong, S.,Mastos, C.,Luo, W.,Qian, C.,Jones, G.D.,Venugopal, H.,Chang, Y.G.,Clarke, R.J.,Halls, M.L.,Ellisdon, A.M. LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR. Nature, 634:1238-1244, 2024 Cited by PubMed Abstract: Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1). However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation. PubMed: 39358511DOI: 10.1038/s41586-024-08012-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.65 Å) |
Structure validation
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