9BOI
Cryo-EM structure of human Spns1 in complex with LPC (18:1)
Summary for 9BOI
| Entry DOI | 10.2210/pdb9boi/pdb |
| EMDB information | 44742 |
| Descriptor | mVenus,Maltose/maltodextrin-binding periplasmic protein,Protein spinster homolog 1,Designed ankyrin repeat protein (DARPin), (4R,7R,18Z)-4,7-dihydroxy-N,N,N-trimethyl-10-oxo-3,5,9-trioxa-4-phosphaheptacos-18-en-1-aminium 4-oxide (2 entities in total) |
| Functional Keywords | lysosome, major facilitator superfamily, lysophospholipid transporter, lysophosphatidylcholine, membrane protein |
| Biological source | Aequorea victoria More |
| Total number of polymer chains | 1 |
| Total formula weight | 139822.38 |
| Authors | |
| Primary citation | Chen, H.,Ha, H.T.T.,Elghobashi-Meinhardt, N.,Le, N.A.,Schmiege, P.,Nguyen, L.N.,Li, X. Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome. Proc.Natl.Acad.Sci.USA, 122:e2409596121-e2409596121, 2025 Cited by PubMed Abstract: Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear. Here, we present a cryogenic electron microscopy structure of human Spns1 in lysophosphatidylcholine (LPC)-bound lumen-facing conformation. Notably, LPC snugly binds within the luminal-open cavity, where the molecular dynamics simulations reveal that LPC presents a propensity to enter between transmembrane-helices (TM) 5 and 8. Structural comparisons and cell-based transport assays uncover several pivotal residues at TM 5/8 that orchestrate the transport cycle, which are unique to Spns1. Furthermore, we identify a five-residue network that is crucial for proton-sensing by Spns1. Transference of these network residues to Spns2, a sphingosine-1-phosphate uniporter, causes the chimeric Spns2 to be low pH dependent. Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1. PubMed: 39739806DOI: 10.1073/pnas.2409596121 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.22 Å) |
Structure validation
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