{"uniprot":"Q6ZMD2","gene":"SPNS3","name":"Protein spinster homolog 3","organism":"Homo sapiens (Human)","status":"dark","length":512,"sequence":"MAGGMSAECPEPGPGGLQGQSPGPGRQCPPPITPTSWSLPPWRAYVAAAVLCYINLLNYMNWFIIAGVLLDIQEVFQISDNHAGLLQTVFVSCLLLSAPVFGYLGDRHSRKATMSFGILLWSGAGLSSSFISPRYSWLFFLSRGIVGTGSASYSTIAPTVLGDLFVRDQRTRVLAVFYIFIPVGSGLGYVLGSAVTMLTGNWRWALRVMPCLEAVALILLILLVPDPPRGAAETQGEGAVGGFRSSWCEDVRYLGKNWSFVWSTLGVTAMAFVTGALGFWAPKFLLEARVVHGLQPPCFQEPCSNPDSLIFGALTIMTGVIGVILGAEAARRYKKVIPGAEPLICASSLLATAPCLYLALVLAPTTLLASYVFLGLGELLLSCNWAVVADILLSVVVPRCRGTAEALQITVGHILGDAGSPYLTGLISSVLRARRPDSYLQRFRSLQQSFLCCAFVIALGGGCFLLTALYLERDETRAWQPVTGTPDSNDVDSNDLERQGLLSGAGASTEEP","function_summary":"A human multi-pass membrane transporter that uses a major facilitator scaffold to move sphingolipid-like lipids across intracellular membranes. By assembling with accessory proteins and operating an alternating-access mechanism, it redistributes sphingolipids between organelles to sustain intracellular lipid balance, thereby supporting both their biosynthesis and broader lipid-transport pathways within membrane-bounded compartments.","plain_language":"SPNS3 has barely been studied. The model's best guess: A human multi-pass membrane transporter that uses a major facilitator scaffold to move sphingolipid-like lipids across intracellular membranes. By assembling with accessory proteins and operating an alternating-access mechanism, it redistributes sphingolipids between organelles to sustain intracellular lipid balance, thereby supporting both their biosynthesis and broader lipid-transport pathways within membrane-bounded compartments.","uniprot_summary":"May be a lipid transporter.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0006869","label":"lipid transport"},{"id":"GO:0006665","label":"sphingolipid metabolic process"},{"id":"GO:0030148","label":"sphingolipid biosynthetic process"}],"cellular_component":[{"id":"GO:0043231","label":"intracellular membrane-bounded organelle"}]},"interpro":[{"id":"IPR036259","name":"MFS transporter superfamily","type":"homologous_superfamily","start":33,"end":469},{"id":"IPR020846","name":"Major facilitator superfamily domain","type":"domain","start":47,"end":477},{"id":"IPR044770","name":"Protein spinster-like","type":"family","start":46,"end":481},{"id":"IPR011701","name":"Major facilitator superfamily","type":"family","start":52,"end":413}],"reasoning":"I begin with the InterPro architecture. The core of the protein is defined by IPR036259 (MFS transporter superfamily, residues 33–469) and IPR020846 (Major facilitator superfamily domain, residues 47–477), which together specify a canonical major facilitator superfamily fold that forms a 12-helix, multi-pass membrane transporter. This scaffold is reinforced by IPR011701 (Major facilitator superfamily, residues 52–413), consolidating the identity of an alternating-access carrier that uses the transmembrane proton or ion gradient to move small amphipathic solutes. Overlaying this transporter framework, IPR044770 (Protein spinster-like family, residues 46–481) narrows the substrate class toward sphingolipids handled by spinster/spinsteryl-related systems. The ordered layout—spinster-like family signature embedded within an MFS core—causally dictates a lipid-transport mechanism rather than enzymatic catalysis.\n\nFrom this architecture, the molecular function resolves as a membrane transporter that binds other proteins to assemble or regulate transport complexes. The MFS fold provides the alternating-access mechanism, while the spinster-like family signature biases substrate preference toward sphingolipids and sterol-sphingolipid conjugates. Such transporters often require accessory partners for trafficking and regulation, which supports GO:0005515 protein binding as an intrinsic capability of this scaffold.\n\nThe biological process follows directly from the substrate class. Sphingolipid handling by spinster-like MFS carriers drives GO:0006869 lipid transport. Because the spinster-like family tunes flux through pathways that balance sphingolipid and sterol-sphingolipid pools, the transporter’s activity feeds into GO:0006665 sphingolipid metabolic process and supports GO:0030148 sphingolipid biosynthetic process by replenishing precursors and maintaining steady-state pools. The causal chain is: MFS-driven translocation of sphingolipid-like solutes adjusts intracellular distribution and turnover, which in turn sustains both biosynthesis and catabolism of sphingolipids.\n\nCellular location is dictated by the multi-pass MFS core and the need to manage cytoplasmic-facing pools of lipids. The absence of soluble domains and the presence of extensive transmembrane segments place the protein as an integral membrane component. Its role in intracellular lipid routing and the provided localization cues point to intracellular membrane-bounded organelles, consistent with GO:0043231 intracellular membrane-bounded organelle, and align with a multi-pass membrane protein topology.\n\nMechanistically, I hypothesize an alternating-access transporter that binds sphingolipid or sterol-sphingolipid conjugates within a central cavity formed by the MFS helices. Proton-coupled conformational changes would shuttle cargo between luminal and cytosolic leaflets of intracellular membranes. To operate efficiently, the transporter likely forms transient assemblies with cytosolic adaptors and trafficking machinery. Candidate partners include clathrin adaptor complexes and lipid-handling modules that chaperone sphingolipids between organelles. These assemblies would stabilize the transporter in the correct membrane, coordinate cargo handoff, and couple lipid flux to broader membrane trafficking pathways.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q6ZMD2.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q6ZMD2"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q6ZMD2/entry","atlas":"/p/Q6ZMD2"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}