SEPSECS (O-phosphoseryl-tRNA(Sec) selenium transferase, also known as selenocysteine synthase / Sec synthase / SepSecS, and historically as the SLA/LP soluble liver antigen) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the terminal step of selenocysteine (Sec) biosynthesis. In archaea and eukaryotes, Sec is uniquely synthesized on its cognate tRNA(Sec): seryl-tRNA(Sec) is phosphorylated by PSTK to O-phospho-L-seryl-tRNA(Sec), which SEPSECS then converts, using selenophosphate (produced by SEPHS2) as the selenium donor, into L-selenocysteinyl-tRNA(Sec) (EC 2.9.1.2). The charged Sec-tRNA(Sec) is subsequently delivered by the specialized elongation factor EEFSEC to recode in-frame UGA codons during translation of selenoprotein mRNAs. SEPSECS assembles into a homotetramer comprising a catalytic dimer and a non-catalytic dimer that acts as a binding platform orienting two tRNA(Sec) molecules for catalysis; the PLP cofactor is covalently bound through a Schiff base to the active-site lysine (Lys284). The enzyme acts specifically on phosphoserine attached to tRNA(Sec), not on free phosphoserine. It localizes to the cytoplasm/cytosol and can associate with other components of the selenocysteine-synthesis machinery (SEPHS1, SEPHS2, TRNAU1AP/SECp43). Loss-of-function mutations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (progressive cerebello-cerebral atrophy), underscoring the requirement for selenoprotein biosynthesis in the developing nervous system.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001514 selenocysteine incorporation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically-inferred involvement in selenocysteine incorporation. SEPSECS charges tRNA(Sec) with Sec, an upstream prerequisite for the downstream ribosomal incorporation of Sec at UGA codons, so this process-level term is biologically appropriate but represents the wider pathway rather than the enzyme's own catalytic step. Retained as non-core. Reason: Correct pathway-level association (the whole Sec machinery serves Sec incorporation), but SEPSECS's specific, core role is tRNA charging (GO:0001717 / GO:0098621), not the ribosomal incorporation event itself. |
| GO:0000049 tRNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: tRNA binding is a genuine, well-established molecular function of SEPSECS: the tetramer binds two tRNA(Sec) molecules through their acceptor-, TPsiC-, and variable arms, and this binding is required for catalysis. Supporting Evidence: PMID:19608919 SepSecS binds only to the acceptor-, TΨC-, and variable arms of tRNASec |
| GO:0001717 conversion of seryl-tRNAsec to selenocys-tRNAsec | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to the specific biological process performed by SEPSECS, the conversion of the (phospho)seryl-charged tRNA(Sec) to the selenocysteinyl form. This is exactly the reaction SEPSECS catalyzes and is independently supported by experimental (IDA) evidence. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl- |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization, consistent with the experimentally determined subcellular location and with the cytosolic selenocysteine-synthesis machinery. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016740 transferase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic InterPro-derived transferase activity. This is a high-level parent of the specific and experimentally supported activity (O-phosphoseryl-tRNA(Sec) selenium transferase activity, GO:0098621) and is uninformative on its own. Reason: Over-general; should be replaced by the specific molecular function that is directly supported by experimental evidence. Proposed replacements: O-phosphoseryl-tRNA(Sec) selenium transferase activity |
| GO:0098621 O-phosphoseryl-tRNA(Sec) selenium transferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to the precise catalytic activity of SEPSECS (EC 2.9.1.2). This is the core molecular function and is corroborated by experimental (IDA) evidence. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt EC=2.9.1.2 |
| GO:0005515 protein binding | IPI PMID:22190034 Global landscape of HIV-human protein complexes. | REMOVE | Summary: IPI annotation from a large-scale HIV-host interactome screen; the recorded partner is the HIV-1 Gag polyprotein (UniProtKB:P04591), a xeno interaction and not a native functional partner. Bare "protein binding" is uninformative about SEPSECS's molecular function. Reason: Uninformative generic term derived from a viral-host (HIV-1 Gag) affinity-capture screen; no specific, biologically meaningful molecular function can be assigned from it. Removal does not mean the interaction is false. |
| GO:0000049 tRNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: tRNA binding transferred electronically from the mouse ortholog; agrees with the experimentally established binding of tRNA(Sec) by human SEPSECS. Supporting Evidence: PMID:19608919 SepSecS binds only to the acceptor-, TΨC-, and variable arms of tRNASec |
| GO:0001514 selenocysteine incorporation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation to the pathway-level process of selenocysteine incorporation. Duplicate of the IBA/IDA/ISS annotations to this term; correct at the pathway level but represents the downstream process rather than SEPSECS's own catalytic step. Reason: Pathway-level involvement; SEPSECS's core, direct role is tRNA(Sec) charging (GO:0001717 / GO:0098621), not the ribosomal incorporation event. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Nuclear localization electronically transferred from the mouse ortholog (Q6P6M7) via Ensembl Compara. There is no experimental support for a nuclear pool of SEPSECS; the enzyme and the selenocysteine-synthesis machinery are cytoplasmic/cytosolic. Reason: Ortholog-transferred location with no experimental support in human; the experimentally determined location is cytoplasm/cytosol, where the Sec-charging pathway operates. Treated the same way as the corresponding ISS row (flagged rather than removed, since a minor nuclear pool has not been excluded experimentally). |
| GO:0005829 cytosol | IPI PMID:36929010 Structural basis for the tRNA-dependent activation of the te... | ACCEPT | Summary: Cytosolic localization assigned by ComplexPortal for the SepSecS-tRNASec complex. Consistent with the cytoplasmic subcellular location and the cytosolic Sec-biosynthesis pathway. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016260 L-selenocysteine biosynthetic process | NAS PMID:19608919 The human SepSecS-tRNASec complex reveals the mechanism of s... | ACCEPT | Summary: Involvement in L-selenocysteine biosynthesis. SEPSECS catalyzes the final step forming selenocysteine (on tRNA(Sec)), so this biosynthetic-process term is a correct and core biological process for the gene. Supporting Evidence: PMID:19608919 SepSecS catalyzes the conversion of the phosphoseryl moiety into the selenocysteinyl group |
| GO:1990234 transferase complex | IPI PMID:36929010 Structural basis for the tRNA-dependent activation of the te... | KEEP AS NON CORE | Summary: Membership in a transferase complex (the SepSecS-tRNASec complex / SepSecS homotetramer), assigned by ComplexPortal. SEPSECS functions as a homotetramer, so complex membership is well supported; retained as a non-core cellular-component annotation. Reason: Correct complex-membership annotation, but a high-level "transferase complex" CC term; the informative core content is the enzymatic activity and the homotetrameric assembly it enables. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt Homotetramer formed by a catalytic dimer and a non-catalytic |
| GO:0001514 selenocysteine incorporation | IDA PMID:17142313 RNA-dependent conversion of phosphoserine forms selenocystei... | KEEP AS NON CORE | Summary: Experimental (IDA) annotation to selenocysteine incorporation. SEPSECS was shown to produce the Sec-tRNA(Sec) required for Sec incorporation, and human SepSecS complements an E. coli Sec-synthase (SelA) deletion in vivo. This supports involvement in the Sec-incorporation process; retained as non-core because SEPSECS's direct step is tRNA charging, upstream of the ribosomal incorporation event. Reason: Experimental evidence supports pathway involvement, but the term denotes the downstream translational incorporation process; the enzyme's own core function is the Sep-to-Sec conversion on tRNA(Sec). Supporting Evidence: PMID:17142313 in vivo an Escherichia coli Sec synthase (SelA) deletion strain |
| GO:0001717 conversion of seryl-tRNAsec to selenocys-tRNAsec | IDA PMID:17142313 RNA-dependent conversion of phosphoserine forms selenocystei... | ACCEPT | Summary: Experimental (IDA) annotation to the exact biological process SEPSECS carries out: converting the (phospho)seryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec). Purified recombinant SepSecS was shown to perform this conversion in vitro. Core biological process. Supporting Evidence: PMID:17142313 purified recombinant SepSecS converts Sep-tRNA(Sec) into Sec-tRNA(Sec) in vitro |
| GO:0005737 cytoplasm | IDA PMID:28414460 Analysis of Novel Interactions between Components of the Sel... | ACCEPT | Summary: Experimentally determined cytoplasmic localization (basis for the UniProt subcellular-location assertion). Core/accepted location. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:28414460} |
| GO:0098621 O-phosphoseryl-tRNA(Sec) selenium transferase activity | IDA PMID:17142313 RNA-dependent conversion of phosphoserine forms selenocystei... | ACCEPT | Summary: Experimental (IDA) annotation to the core catalytic activity of SEPSECS (EC 2.9.1.2). Purified recombinant SepSecS converts Sep-tRNA(Sec) to Sec-tRNA(Sec) using selenophosphate as the selenium donor. This is the defining molecular function of the gene. Supporting Evidence: PMID:17142313 purified recombinant SepSecS converts Sep-tRNA(Sec) into Sec-tRNA(Sec) in vitro |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2408555 | ACCEPT | Summary: Cytosolic localization asserted by Reactome for the reaction in which the SEPSECS tetramer converts Sep-tRNA(Sec) to Sec-tRNA(Sec). Consistent with the experimentally determined cytoplasmic location. Supporting Evidence: Reactome:R-HSA-2408555 O-phosphoseryl-tRNA(Sec) selenium transferase (SEPSECS) tetramer catalyses the transformation of phosphoserine (Sep) into selenocysteine (Sec) |
| GO:0000049 tRNA binding | TAS PMID:10801173 Identification of target antigen for SLA/LP autoantibodies i... | ACCEPT | Summary: tRNA binding annotation traceable to the identification of SEPSECS (SLA/LP) as the protein component of the tRNA(Ser)Sec ribonucleoprotein (tRNP(Ser)Sec) complex. SEPSECS is a bona fide tRNA(Sec)-binding protein; the association with the tRNA(Sec)-containing particle is the historical basis for this term. Supporting Evidence: PMID:10801173 suggested to be UGA-suppressor |
| GO:0000049 tRNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: tRNA binding inferred by sequence similarity from the mouse ortholog (Q6P6M7); concordant with the experimentally established binding of tRNA(Sec) by human SEPSECS. Supporting Evidence: PMID:19608919 SepSecS binds only to the acceptor-, TΨC-, and variable arms of tRNASec |
| GO:0001514 selenocysteine incorporation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Selenocysteine incorporation inferred by sequence similarity from the mouse ortholog. Duplicate of the IBA/IDA/IEA annotations; correct at the pathway level but downstream of SEPSECS's direct tRNA-charging step. Reason: Pathway-level process; SEPSECS's core function is the Sep-to-Sec conversion on tRNA(Sec) rather than ribosomal Sec incorporation. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Nuclear localization inferred by sequence similarity from the mouse ortholog (Q6P6M7). Not supported by experimental data for human SEPSECS, which is cytoplasmic/cytosolic. Likely an over-annotation of an orthology-transferred location. Reason: No experimental support for a nuclear pool; the enzyme acts in the cytosolic selenocysteine-synthesis pathway. Orthology-transferred (ISS) rather than clearly-wrong IEA, hence flagged rather than removed. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic localization inferred by sequence similarity from the mouse ortholog; concordant with the experimentally determined location of human SEPSECS. Supporting Evidence: file:human/SEPSECS/SEPSECS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0030170 pyridoxal phosphate binding | IDA PMID:19608919 The human SepSecS-tRNASec complex reveals the mechanism of s... | NEW | Summary: Proposed annotation (not in GOA). The crystal structure of human SepSecS shows PLP covalently bound as an internal aldimine to the conserved active-site Lys284 in every monomer; PLP is the obligatory catalytic cofactor of the Sep-to-Sec conversion. Reason: Direct structural evidence for PLP binding by human SEPSECS; this cofactor binding is integral to its core catalytic activity and is listed as a core function. Supporting Evidence: PMID:19608919 Each SepSecS monomer has a PLP cofactor covalently linked to the NΞ΅-amino group of the conserved Lys284 |
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Download this section (compressed HTML)Q: Is there any physiologically relevant regulation of SEPSECS activity (e.g. by phosphorylation at Ser14, or by selenium status), or is flux through the Sec pathway controlled entirely upstream (SEPHS2/PSTK)?
Q: Do the reported associations with SEPHS1, SEPHS2 and TRNAU1AP (SECp43) represent a stable channeling complex in vivo, or transient interactions?
Experiment: Quantitative in vitro kinetic characterization of purified human SEPSECS with defined Sep-tRNA(Sec) and selenophosphate substrates, including PCH2D variants (A239T, T325S, Y334C), to relate residual catalytic activity to disease severity.
Experiment: Endogenous subcellular fractionation and proximity-labeling (e.g. BioID) in human neuronal cells to define the SEPSECS interactome and confirm the exclusively cytosolic localization.
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