Serinc (CG4672; also called DmSERINC or TMS1) is the single Drosophila member of the SERINC/TMS (TDE1) family of multipass integral membrane proteins. M9PCT1 is the 458-residue isoform C, one of six splice products that share the same ten-helix membrane core and differ by short indels in a cytosolic loop or, for isoform F, an alternative C-terminal segment. Cryo-EM of the purified fly protein shows protomers of ten transmembrane helices arranged in two subdomains around a diagonal helix, with cytoplasmic N and C termini, two extracellular disulphides, and a groove in subdomain B that holds an acyl chain. Phosphatidylserine, cholesterol and sulfatide stabilise the purified protein, and phosphatidylserine alters hydrogen/deuterium exchange around that groove. The purified fly protein forms hexamers held together largely by lipid, including cardiolipin. When expressed in human cells, DmSERINC reduces the infectivity of Nef-deficient HIV-1, as human SERINC5 does. Its native lipid-transport activity, subcellular compartment and physiological role in the fly have not been determined. The family name comes from an early proposal of serine incorporation into lipids, which later work has not upheld.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Serinc isoform C is an integral multipass membrane protein; membrane is the most specific location the evidence supports. Reason: The cryo-EM structure of DmSERINC resolves ten transmembrane helices. M9PCT1 keeps the whole membrane core, including every structurally named residue and both disulphides (Serinc-bioinformatics/RESULTS.md), and Phobius predicts multiple transmembrane segments for this exact accession. The PAINT IBD for PTHR10383 sits at the eukaryotic root (PTN000043695) and is also only GO:0016020. No fly experiment places the native protein in a specific compartment. Human SERINC5 at the plasma membrane is in a different subfamily (SF16), and yeast TMS1 at the vacuole is a distant SF9 member, so neither location transfers. The generic term is therefore kept rather than refined. Supporting Evidence: PMID:31907454 Each of the six identical DmSERINC subunits consists of ten transmembrane helices (TM) arranged into two subdomains file:DROME/Serinc/Serinc-uniprot.txt FT TRANSMEM 38..58 file:genes/DROME/Serinc/Serinc-flybase.txt Serinc-PC FBpp0302688 49.4 458 5.57 M9PCT1 NP_001261949 AGB94642 file:DROME/Serinc/Serinc-bioinformatics/RESULTS.md M9PCT1 carries all 18 named residues |
| GO:0008289 lipid binding | IDA PMID:31907454 A bipartite structural organization defines the SERINC famil... | NEW | Summary: Purified DmSERINC binds lipids directly. An acyl chain occupies the subdomain-B groove in the cryo-EM map, cardiolipin is bound at the protomer interfaces, phosphatidylserine, cholesterol and sulfatide raise its thermostability, and phosphatidylserine alters HDX around the groove. Reason: These are direct biochemical and structural observations on the purified fly protein. The structure and HDX numbering follows isoform A, but M9PCT1 is identical to it except for a 7-residue cytosolic-loop deletion and carries the whole groove (Serinc-bioinformatics/RESULTS.md). The generic lipid-binding term is used rather than phosphatidylserine binding because several lipids stabilise the protein and no binding constant or specificity was measured. Cardiolipin probably came from the yeast expression host and mediates hexamer contacts, so it is not proposed as a specific ligand. Phospholipid scramblase activity (GO:0017128) is not proposed. It has been shown for human SERINC3/5 (PMID:37474505), which sit in other PANTHER subfamilies (SF51/SF16). The PAINT curators propagated only membrane from the family root and not scramblase or any process term, and no lipid-transport assay has been done on the fly protein. Supporting Evidence: PMID:31907454 the cryo-EM map revealed presence of an acyl chain bound at this site PMID:31907454 addition of phosphatidylserine, cholesterol or sulfatide increased DmSERINC and SERINC5 protein thermostability PMID:31907454 hydrogen/deuterium exchange (HDX) experiments with DmSERINC revealed that phosphatidylserine affected isotope exchange around the potential lipid binding groove in subdomain B |
Loading supporting content…
Download this section (compressed HTML)Q: Does purified DmSERINC scramble phospholipids in proteoliposomes as human SERINC3/5 do? Should PAINT then place phospholipid scramblase activity at a node above SF9, or is that activity specific to the vertebrate subfamilies?
Q: Is the hexamer, bridged by cardiolipin from the yeast host, present in native fly membranes, or is it a feature of detergent purification?
Experiment: Reconstitute purified DmSERINC (isoform C and isoform F, which has a different C-terminal segment) into proteoliposomes and measure ATP-independent flipping of NBD-labelled PS, PE and PC.
Type: in vitro lipid scrambling assay
Experiment: Tag endogenous Serinc by CRISPR knock-in and co-localise it with plasma membrane, ER, Golgi and endolysosomal markers in fly tissues to establish its native compartment.
Type: endogenous tagging and imaging
Loading supporting content…
Download this section (compressed HTML)TMS1 (TMS1) encodes a putative L-serine transmembrane transporter.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)