SCP2

Summary: Peroxisome is the primary site of action for both SCPx (thiolase) and the imported SCP2 transfer protein. Well supported by phylogenetic inference and by direct evidence; a core localization.

Summary: General 3-ketoacyl-CoA thiolase (acetyl-CoA C-acyltransferase) activity of the SCPx thiolase domain. Correct in essence, but SCPx's physiologically distinctive activity is the branched-chain / bile-acid thiolase step; this broad term is kept as a non-core parent of the more specific activity.

Summary: Cytoplasm annotation from Swiss-Prot subcellular location mapping. The SCP2 transfer protein is indeed found in the cytosol (also supported by EXP annotations below), consistent with its lipid-trafficking role. Non-core.

Summary: Mitochondrion from subcellular-location mapping. SCP2 has a putative N-terminal mitochondrial-type presequence and a minor mitochondrial pool has been reported, but this is not a core site of function; likely an over-annotation of a peroxisomal/cytosolic lipid-transfer protein. ORGANELLES re-check (2026-11-03) revises this to non-core.

Reason: ORGANELLES check (2026-11-03). SL-0173 maps UniProt's curated Mitochondrion for isoform SCP2, tagged ECO:0000269 to PMID:17157249 and ECO:0000250 to mouse P32020 (the EXP and ISS rows below). The PMID:17157249 tag is not supported by that paper (see the EXP row's source defect), so the IEA effectively rests on the mouse evidence. The mitochondrial pool belongs to the 15 kDa SCP2 isoform (P22307-2); UniProt locates SCPx to the peroxisome only. Lines for the organelle claim: mouse MA-10 cells and testis (PMID:26901662), where endogenous SCP2 is found in a crude mitochondrial fraction and co-stains with VDAC1, the UniProt mouse entry P32020 curating Mitochondrion to PMID:11003606 and PMID:26901662, and MitoCarta3.0 (Broad file of 2026-10-25), which lists human SCP2 (MS/MS in nine mouse tissues, score "50-75crude"). The mouse fraction was not checked for an ER marker, and SCP2 is also reported on the ER, so the signal cannot exclude MAM; with two further independent lines the claim is kept as a minor, non-core pool (DTYMK/CKB precedent) rather than over-annotated. Stay at the root: MitoCarta3.0's "MIM" call is the only sub-mitochondrial line, and PMID:26901662 found the predicted N-terminal presequence unable to target a reporter to mitochondria.

Summary: Peroxisome from subcellular-location mapping. Consistent with the core localization; redundant with the IDA/IBA/ISS peroxisome annotations.

Summary: ER from the UniProt subcellular-location keyword, which here derives from the mouse P32020 similarity statement for isoform SCP2; a minor, non-core pool of the soluble sterol carrier.

Reason: ORGANELLES check (2026-11-05). SL-0095 maps UniProt's [Isoform SCP2] "Endoplasmic reticulum" line, tagged ECO:0000250 to mouse P32020, so this row has the same single basis as the ISS row: confocal double labelling of overexpressed SCP-2 in mouse L-cell fibroblasts (PMID:11003606), with microsomal phosphatidic acid synthesis data as a functional link. Kept as non-core for the reasons given on the ISS row (close call against MARK_AS_OVER_ANNOTATED, stated there); a soluble PTS1 protein, so it stays at the root. The isoform restriction (P22307-2) is recorded as a source defect on the ISS row.

Summary: Bile acid metabolic process (ARBA electronic). SCPx catalyzes the thiolytic side-chain cleavage of the bile-acid intermediates DHCA/THCA, so this is correct; a more specific bile acid biosynthetic process annotation also exists.

Summary: Sterol transport (ARBA). Consistent with the SCP2 domain's role as a sterol/cholesterol carrier; correct process for the transfer function.

Summary: Very general acyltransferase activity from InterPro (thiolase-like fold). A correct but uninformative parent of the specific thiolase activity; superseded by the more precise MF terms.

Summary: General acyltransferase (non-amino-acyl) activity from InterPro thiolase signatures. Correct but uninformative parent term; superseded by the specific thiolase MF.

Summary: Regulation of lipid metabolic process (ARBA). SCP2 influences lipid metabolism (e.g. phospholipid synthesis in the ER, steroidogenesis) but this broad regulatory term is not a core function and is only weakly specific.

Summary: Fatty acid oxidation (ARBA). Correct — SCPx performs the thiolytic step of peroxisomal beta-oxidation. A more specific fatty acid beta-oxidation annotation also exists; kept as a non-core parent.

Summary: Propanoyl-CoA C-acyltransferase (RHEA/EC 2.3.1.176) is the bile-acid thiolase reaction (choloyl-CoA + propanoyl-CoA), catalyzed by SCPx. Correct MF for the bile-acid step; closely related to the branched-chain thiolase core activity.

Summary: This is the branched-chain 3-oxopristanoyl-CoA thiolase reaction (4,8,12-trimethyltridecanoyl-CoA + propanoyl-CoA), the distinctive activity of SCPx. This RHEA-based IEA is redundant with, and supported by, the EXP annotations for the same term. A core molecular function.

Summary: Acetyl-CoA C-myristoyltransferase (EC 2.3.1.155) reflects the SCPx thiolase's in-vitro activity on medium/long straight-chain 3-oxoacyl-CoAs. Correct chemistry but a chain-length variant of the general thiolase activity, not the physiologically distinctive branched-chain role; non-core.

Summary: Bare protein binding IPI recording the SCP2–caveolin-1 interaction. The interaction is real and relevant to cholesterol/PI trafficking to caveolae, but the uninformative GO:0005515 term does not capture a function, so it is removed (the interaction itself is not disputed). See notes for the specific caveolin-1 interaction.

Summary: Bare protein binding from a high-throughput next-generation-sequencing Y2H interactome dataset (partner TRIP13/Q15645). Uninformative and not a core function; removed.

Summary: Bare protein binding from a proteome-scale binary interactome map (partner TRIP13/Q15645). Uninformative high-throughput interaction; removed.

Summary: Bile acid biosynthetic process (Reactome). SCPx performs the peroxisomal thiolytic side-chain cleavage of C27 bile-acid intermediates (DHCA/THCA) that yields the mature C24 bile acids. A core biological process.

Summary: Peroxisomal (acyl-CoA-oxidase) beta-oxidation of pristanoyl-CoA (Reactome). SCPx provides the thiolase step of this pathway. Correct; more specific than the generic fatty acid beta-oxidation term. Non-core specialization of the beta-oxidation role.

Summary: Alpha-linolenic acid (ALA) metabolism (Reactome), reflecting SCPx's role in the peroxisomal beta-oxidation of C24:6n-3 during DHA synthesis. A genuine but peripheral contribution; non-core.

Summary: Peroxisome by immunofluorescence (HPA). Directly supports the core peroxisomal localization.

Summary: General 3-ketoacyl-CoA thiolase activity by similarity to rat SCP2 (P11915). Correct but a broad parent of the specific branched-chain thiolase; non-core.

Summary: Experimental cytoplasm/cytosol localization. Consistent with SCPx remaining stable and active in the cytosol (e.g. in Zellweger fibroblasts that lack functional peroxisomes) and with the transfer protein's cytosolic pool. Non-core relative to the peroxisomal site of catalysis.

Summary: Experimental cytoplasm localization (SCP2). Newly synthesized SCP2/preSCP2 resides in the cytosol before PTS1/PEX5-dependent peroxisomal import. Correct; non-core.

Summary: Mitochondrion by similarity (rat P32020). Only a minor mitochondrial pool is reported (SCP2 has a putative mitochondrial presequence); not a core site. The donor P32020 is the mouse entry, not rat. ORGANELLES re-check (2026-11-03) revises this to non-core.

Reason: ORGANELLES check (2026-11-03). The ISS donor is mouse SCP2 (P32020), whose UniProt entry curates [Isoform SCP2] Mitochondrion to PMID:11003606 (abstract-only, title about ER localization) and PMID:26901662 (full text cached), so the transfer has experimental grounding on the ortholog. The mitochondrial pool belongs to the 15 kDa SCP2 isoform (P22307-2); UniProt locates SCPx to the peroxisome only. Lines for the organelle claim: mouse MA-10 cells and testis (PMID:26901662), where endogenous SCP2 is found in a crude mitochondrial fraction and co-stains with VDAC1, the UniProt mouse entry P32020 curating Mitochondrion to PMID:11003606 and PMID:26901662, and MitoCarta3.0 (Broad file of 2026-10-25), which lists human SCP2 (MS/MS in nine mouse tissues, score "50-75crude"). The mouse fraction was not checked for an ER marker, and SCP2 is also reported on the ER, so the signal cannot exclude MAM; with two further independent lines the claim is kept as a minor, non-core pool (DTYMK/CKB precedent) rather than over-annotated. Stay at the root: MitoCarta3.0's "MIM" call is the only sub-mitochondrial line, and PMID:26901662 found the predicted N-terminal presequence unable to target a reporter to mitochondria.

Summary: Experimental mitochondrion localization from the same study describing a putative N-terminal mitochondrial transit peptide in SCP2. Only a minor secondary pool is reported; this is not a core site of function for a peroxisomal/cytosolic lipid-transfer protein, so it is treated as an over-annotation (consistent with the IEA/ISS mitochondrion annotations). ORGANELLES re-check (2026-11-03) corrects this: the cached full text of PMID:17157249 never mentions mitochondria, and its leader peptide is described as cleaved after peroxisomal import.

Reason: ORGANELLES check (2026-11-03). PMID:17157249 (Stanley et al. 2006, full text cached, including Experimental Procedures) is a structural study of PEX5 binding SCP2 as a PTS1 cargo. The word "mitochondria" never occurs in it; its cell experiment is GFP fused to mature SCP2 (which lacks the 20-residue leader) in fibroblasts, giving cytosol and peroxisomes; and it says the leader is cleaved after peroxisomal import. The paper therefore supports the Cytoplasm tag that UniProt attaches to it but not Mitochondrion, recorded below as a source defect. The row is kept, with the same action as the IEA and ISS rows, because the organelle claim stands on other evidence. The mitochondrial pool belongs to the 15 kDa SCP2 isoform (P22307-2); UniProt locates SCPx to the peroxisome only. Lines for the organelle claim: mouse MA-10 cells and testis (PMID:26901662), where endogenous SCP2 is found in a crude mitochondrial fraction and co-stains with VDAC1, the UniProt mouse entry P32020 curating Mitochondrion to PMID:11003606 and PMID:26901662, and MitoCarta3.0 (Broad file of 2026-10-25), which lists human SCP2 (MS/MS in nine mouse tissues, score "50-75crude"). The mouse fraction was not checked for an ER marker, and SCP2 is also reported on the ER, so the signal cannot exclude MAM; with two further independent lines the claim is kept as a minor, non-core pool (DTYMK/CKB precedent) rather than over-annotated. Stay at the root: MitoCarta3.0's "MIM" call is the only sub-mitochondrial line, and PMID:26901662 found the predicted N-terminal presequence unable to target a reporter to mitochondria.

Summary: Peroxisome by similarity (rat P11915). Redundant support for the core peroxisomal localization.

Summary: ER by similarity to mouse P32020 (isoform SCP2), whose ER statement rests on confocal double-labelling of overexpressed SCP-2 in L-cell fibroblasts; a minor, non-core pool of the soluble sterol carrier.

Reason: ORGANELLES check (2026-11-05). The ISS donor is mouse P32020 (not rat, as an earlier summary said), whose [Isoform SCP2] "Endoplasmic reticulum" line is tagged ECO:0000269 to PMID:11003606 alone (UniProt REST, 2026-11-05). That paper's abstract (cache abstract-only) reports immunofluorescence double labelling in L-cell fibroblasts stably overexpressing SCP-2, ranking the ER second after peroxisomes, and SCP-2 stimulation of microsomal phosphatidic acid synthesis in vitro. SCP2 is a soluble protein with a C-terminal PTS1 (AKL), no signal peptide and no TM segment, so any ER pool is on the cytosolic face and stays at the root; no membrane or lumen row. Close call between KEEP_AS_NON_CORE and MARK_AS_OVER_ANNOTATED: the location rests on an overexpressed protein (weaker than endogenous staining), but a soluble carrier is not subject to the ER retention artefact of overexpressed membrane proteins, the microsomal transacylation data give a functional ER link, and the 2016 mouse study (PMID:26901662) also cites ER pools, so the minor pool is kept as non-core. The ER location belongs to isoform SCP2 (P22307-2), not the displayed SCPx; recorded as a source defect.

Summary: Branched-chain 3-oxopristanoyl-CoA thiolase activity by similarity (rat P11915). Core molecular function; redundant with the EXP annotations for this term.

Summary: Acetyl-CoA C-myristoyltransferase by similarity. A straight-chain thiolase variant of the general activity, not the distinctive branched-chain role; non-core.

Summary: Experimental branched-chain thiolase activity of SCPx, here in the context of peroxisomal beta-oxidation contributing to DHA synthesis. Supports the core thiolase molecular function.

Summary: Experimental thiolase activity of SCPx: patient fibroblasts with SCPx deficiency showed absent thiolytic activity and no SCPx protein. Strong loss-of -function support for the core branched-chain thiolase molecular function.

Summary: Foundational experimental demonstration that SCPx is the branched-chain beta-ketothiolase specifically reacting with 3-oxopristanoyl-CoA. Core molecular function.

Summary: Reactome TAS for the SCPx-catalyzed thiolytic step (trihydroxy-cholestanoyl thiolysis to choloyl-CoA + propionyl-CoA). Supports the core thiolase MF.

Summary: Reactome TAS for the analogous SCPx thiolytic step in chenodeoxycholoyl-CoA formation. Supports the core thiolase MF.

Summary: Fatty acid beta-oxidation by similarity. SCPx catalyzes the thiolytic step of peroxisomal beta-oxidation; a core biological process.

Summary: Bile acid metabolic process by similarity. SCPx cleaves the DHCA/THCA bile-acid intermediate side chains; correct. Redundant with the Reactome bile acid biosynthetic process annotation. Non-core parent.

Summary: Cytosol (Reactome) — the compartment from which PEX5 cargo (including SCP2) translocates into the peroxisomal matrix. Correct pre-import location; non-core.

Summary: Cytosol (Reactome), from the PEX5:cargo docking-complex step. Correct pre-import location; non-core. Redundant with the other cytosol annotation.

Summary: Generic membrane from a high-throughput NK-cell membrane-proteome mass-spec study. SCP2 is a soluble lipid-transfer protein that transiently associates with membranes; this uninformative, contaminant-prone location is an over-annotation.

Summary: Peroxisomal matrix (Reactome) — the precise compartment where the SCPx thiolase and imported SCP2 act. A more specific and accurate version of the peroxisome localization; core.

Summary: Peroxisomal matrix (Reactome), same accurate compartment. Redundant with the other peroxisomal matrix annotations; core.

Summary: Peroxisomal matrix (Reactome), from the 3-ketopristanoyl-CoA thiolysis step. Accurate core compartment; redundant.

Summary: Fatty-acyl-CoA binding (IDA). SCP2 binds fatty acyl-CoAs; this underpins its role as a fatty-acyl-CoA carrier. A genuine ligand-binding MF that supports the transfer function; kept as non-core (binding, not the transfer activity itself).

Summary: Oleic acid binding (IDA). A specific fatty-acid ligand of SCP2, consistent with its broad lipid-binding pocket. Supporting ligand-binding detail; non-core.

Summary: Cholesterol binding (IDA). Direct binding of cholesterol by SCP2 is central to its sterol-carrier function; the presequence study cross-links free cholesterol into the ligand-binding site. Supports the transfer activity; kept as non-core binding term.

Summary: Lipid hydroperoxide transport (IDA). SCP-2 facilitates intermembrane transfer of cholesterol- and phospholipid-derived hydroperoxides in vitro, a genuine extension of its lipid-transfer activity but a peripheral (pathological) process; non-core.

Summary: Positive regulation of intracellular cholesterol transport (IDA). Reflects SCP2's stimulation of intermembrane cholesterol movement. Related to its core lipid-transfer role but framed as regulation; kept as non-core.

Summary: Long-chain fatty acyl-CoA binding (IDA), directly demonstrated by native mass spectrometry (LCFA-CoAs are high-affinity ligands; LCFA-carnitines are not). A specific ligand-binding MF supporting the fatty-acyl-CoA carrier function; non-core.

Summary: Part of a protein-containing complex (IDA), from a SAXS study of the PEX5.PEX14.SCP2 (PTS1-cargo) import complex. This reflects SCP2 as a transient import cargo rather than a stable functional complex subunit; uninformative generic complex term, marked over-annotated.

Summary: Signaling receptor binding IPI, with partner PEX5 (P50542). PEX5 is the peroxisomal PTS1 import receptor, not a signaling receptor; this is the import-cargo–receptor interaction. The MF term mischaracterizes the interaction, and PEX5 recognition is not an evolved core function of SCP2 (it is a targeting-signal recognition event). Removed as a mischaracterized molecular function; the cargo-receptor interaction itself is real.

Reason: The annotated partner is PEX5, the import receptor for peroxisomal matrix proteins that carry a PTS1 signal. PEX5 is not a signaling receptor, so the term misdescribes the interaction. The interaction itself is real: SCP2 is a PTS1 cargo recognised by PEX5. Being recognised as cargo by an import receptor is not a molecular function of SCP2, and no informative term describes the cargo side of that interaction, so the row is removed rather than redirected to another binding term.

Summary: Bare protein binding IPI, partner PEX5 (P50542), from the PEX5.PEX14.SCP2 import-complex SAXS study. Real interaction (SCP2 as PTS1 cargo) but the uninformative GO:0005515 term does not capture function; removed (SCP2 is PEX5 cargo, not a PEX5 regulator).

Summary: Peroxisome by direct assay (GFP-SCP2 import into peroxisomes in fibroblast complementation). Strong direct support for the core peroxisomal localization.

Summary: Peroxisome by direct assay (immunoblotting + subcellular fractionation localizing nsLTP to peroxisomes). Direct support for the core peroxisomal localization.

Summary: Peroxisomal matrix (Reactome), from the DHA-CoA formation step catalyzed by SCPx. Accurate core compartment; redundant.

Summary: Peroxisomal matrix (Reactome), the destination of PEX5 cargo translocation. Accurate core compartment; redundant with other peroxisomal matrix annotations.