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TitleMolecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 5, Page 905-913, Year 2025
Publish dateJan 17, 2025
AuthorsQi Xiong / Zhini Zhu / Tingting Li / Xiaotian Li / Zixuan Zhou / Yulin Chao / Chuanhui Yang / Suihan Feng / Qianhui Qu / Dianfan Li /
PubMed AbstractLysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, ...Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.
External linksNat Struct Mol Biol / PubMed:39824977
MethodsEM (single particle)
Resolution2.11 Å
Structure data

39851

8z8z

EMDB-39851, PDB-8z8z:
Cryo-EM structure of LYCHOS
Method: EM (single particle) / Resolution: 2.11 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

PDB-1l1c:
Structure of the LicT Bacterial Antiterminator Protein in Complex with its RNA Target

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Lysosome / GPCR-like / Transporter / Cholesterol

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