SCP2 is a complex bifunctional gene that produces two protein products from a single locus by alternative promoter usage and processing, both sharing a common C-terminal SCP2 (sterol-carrier) domain. The larger product, SCPx (SCP-x, 58 kDa), is a peroxisomal 3-ketoacyl-CoA thiolase in which an N-terminal thiolase domain is fused to the C-terminal SCP2 domain; it catalyzes the thiolytic-cleavage (last) step of peroxisomal beta-oxidation for 2-methyl branched-chain fatty acids (pristanic acid) and the C27 bile-acid intermediates di- and trihydroxycoprostanic acid (DHCA/THCA), handling substrates that the conventional peroxisomal thiolase (ACAA1) cleaves poorly. The smaller product, SCP2 (nonspecific lipid-transfer protein, nsLTP, ~13 kDa mature), corresponds to the SCP2 domain alone and is an intracellular sterol/phospholipid/fatty-acyl-CoA carrier that transfers cholesterol and phospholipids between membranes and binds long-chain fatty acyl-CoAs. Both products carry a C-terminal type-1 peroxisomal targeting signal (AKL) and are imported into the peroxisomal matrix via PEX5; the transfer protein is also found in the cytosol and endoplasmic reticulum. In humans, loss of SCP2/SCPx function causes a leukoencephalopathy with dystonia and motor neuropathy, accompanied by accumulation of pristanic acid and abnormal bile-alcohol glucuronides.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005777 peroxisome | IBA GO_REF:0000033 | ACCEPT | 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. Supporting Evidence: PMID:1347505 non-specific lipid transfer protein (nsLTP), another peroxisomal protein synthesised as a larger precursor, is localised in peroxisomes |
| GO:0003988 acetyl-CoA C-acyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. Supporting Evidence: PMID:9245689 SCPx, a 58 kDa protein with both thiolase and sterol carrier protein activity but unknown function so far, readily reacts with 3-oxopristanoyl-CoA |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | 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. |
| GO:0005777 peroxisome | IEA GO_REF:0000044 | ACCEPT | Summary: Peroxisome from subcellular-location mapping. Consistent with the core localization; redundant with the IDA/IBA/ISS peroxisome annotations. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ER from subcellular-location mapping. The SCP2 transfer protein acts at/near the ER in lipid trafficking (e.g. ER-to-plasma-membrane cholesterol transfer), so this is a reasonable secondary location. Non-core. |
| GO:0008206 bile acid metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | 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. Supporting Evidence: file:human/SCP2/SCP2-uniprot.txt Catalyzes the last step of the peroxisomal beta-oxidation of branched chain fatty acids and the side chain of the bile acid intermediates di- and trihydroxycoprostanic acids (DHCA and THCA) |
| GO:0015918 sterol transport | IEA GO_REF:0000117 | ACCEPT | Summary: Sterol transport (ARBA). Consistent with the SCP2 domain's role as a sterol/cholesterol carrier; correct process for the transfer function. Supporting Evidence: PMID:15449949 Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid (PL) transfer/exchange between membranes |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: General acyltransferase (non-amino-acyl) activity from InterPro thiolase signatures. Correct but uninformative parent term; superseded by the specific thiolase MF. |
| GO:0019216 regulation of lipid metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | 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. |
| GO:0019395 fatty acid oxidation | IEA GO_REF:0000117 | KEEP AS NON CORE | 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. |
| GO:0033814 propanoyl-CoA C-acyltransferase activity | IEA GO_REF:0000116 | ACCEPT | 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. Supporting Evidence: PMID:10706581 Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | IEA GO_REF:0000116 | ACCEPT | 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. Supporting Evidence: PMID:9245689 SCPx, a 58 kDa protein with both thiolase and sterol carrier protein activity but unknown function so far, readily reacts with 3-oxopristanoyl-CoA |
| GO:0050633 acetyl-CoA C-myristoyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. |
| GO:0005515 protein binding | IPI PMID:15182174 Sterol carrier protein-2 directly interacts with caveolin-1 ... | MARK AS OVER ANNOTATED | 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; marked over-annotated. See notes for the specific caveolin-1 interaction. Supporting Evidence: PMID:15182174 SCP-2 (but not PITP) selectively interacted with caveolin-1, both within the cytoplasm and at the plasma membrane |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a high-throughput next-generation-sequencing Y2H interactome dataset (partner TRIP13/Q15645). Uninformative and not a core function; marked over-annotated. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a proteome-scale binary interactome map (partner TRIP13/Q15645). Uninformative high-throughput interaction; marked over-annotated. |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193368 | ACCEPT | 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. Supporting Evidence: file:human/SCP2/SCP2-uniprot.txt Catalyzes the last step of the peroxisomal beta-oxidation of branched chain fatty acids and the side chain of the bile acid intermediates di- and trihydroxycoprostanic acids (DHCA and THCA) |
| GO:0033540 fatty acid beta-oxidation using acyl-CoA oxidase | TAS Reactome:R-HSA-389887 | KEEP AS NON CORE | 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. Supporting Evidence: PMID:9245689 SCPx plays a central role in branched chain fatty acid beta-oxidation in peroxisomes |
| GO:0036109 alpha-linolenic acid metabolic process | TAS Reactome:R-HSA-2046106 | KEEP AS NON CORE | 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. Supporting Evidence: PMID:11734571 the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx |
| GO:0005777 peroxisome | IDA GO_REF:0000052 | ACCEPT | Summary: Peroxisome by immunofluorescence (HPA). Directly supports the core peroxisomal localization. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. |
| GO:0005737 cytoplasm | EXP PMID:10706581 Peroxisomal fatty acid oxidation disorders and 58 kDa sterol... | KEEP AS 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. |
| GO:0005737 cytoplasm | EXP PMID:17157249 Recognition of a functional peroxisome type 1 target by the ... | KEEP AS NON CORE | Summary: Experimental cytoplasm localization (SCP2). Newly synthesized SCP2/preSCP2 resides in the cytosol before PTS1/PEX5-dependent peroxisomal import. Correct; non-core. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Mitochondrion by similarity (rat P32020). Only a minor mitochondrial pool is reported (SCP2 has a putative mitochondrial presequence); not a core site. |
| GO:0005739 mitochondrion | EXP PMID:17157249 Recognition of a functional peroxisome type 1 target by the ... | MARK AS OVER ANNOTATED | 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). |
| GO:0005777 peroxisome | ISS GO_REF:0000024 | ACCEPT | Summary: Peroxisome by similarity (rat P11915). Redundant support for the core peroxisomal localization. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ER by similarity (rat P32020). Consistent with the transfer protein acting at the ER in lipid trafficking; non-core. |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Branched-chain 3-oxopristanoyl-CoA thiolase activity by similarity (rat P11915). Core molecular function; redundant with the EXP annotations for this term. |
| GO:0050633 acetyl-CoA C-myristoyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Acetyl-CoA C-myristoyltransferase by similarity. A straight-chain thiolase variant of the general activity, not the distinctive branched-chain role; non-core. |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | EXP PMID:11734571 Identification of the peroxisomal beta-oxidation enzymes inv... | ACCEPT | 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. Supporting Evidence: PMID:11734571 the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | EXP PMID:16685654 Mutations in the gene encoding peroxisomal sterol carrier pr... | ACCEPT | 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. Supporting Evidence: PMID:16685654 In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | EXP PMID:9245689 Sterol carrier protein X (SCPx) is a peroxisomal branched-ch... | ACCEPT | Summary: Foundational experimental demonstration that SCPx is the branched-chain beta-ketothiolase specifically reacting with 3-oxopristanoyl-CoA. Core molecular function. Supporting Evidence: PMID:9245689 the conventional peroxisomal thiolase which has so far been thought to catalyze the thiolytic cleavage of the 3-oxoacyl-CoA esters of all fatty acids oxidized in peroxisomes, shows poor reactivity towards the 3-oxoacyl-CoA esters of 2-methyl branched-chain fatty acids such as pristanic acid |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | TAS Reactome:R-HSA-192341 | ACCEPT | Summary: Reactome TAS for the SCPx-catalyzed thiolytic step (trihydroxy-cholestanoyl thiolysis to choloyl-CoA + propionyl-CoA). Supports the core thiolase MF. |
| GO:0050632 propionyl-CoA C2-trimethyltridecanoyltransferase activity | TAS Reactome:R-HSA-193533 | ACCEPT | Summary: Reactome TAS for the analogous SCPx thiolytic step in chenodeoxycholoyl-CoA formation. Supports the core thiolase MF. |
| GO:0006635 fatty acid beta-oxidation | ISS GO_REF:0000024 | ACCEPT | Summary: Fatty acid beta-oxidation by similarity. SCPx catalyzes the thiolytic step of peroxisomal beta-oxidation; a core biological process. Supporting Evidence: PMID:9245689 SCPx plays a central role in branched chain fatty acid beta-oxidation in peroxisomes |
| GO:0008206 bile acid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033235 | KEEP AS NON CORE | Summary: Cytosol (Reactome) — the compartment from which PEX5 cargo (including SCP2) translocates into the peroxisomal matrix. Correct pre-import location; non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033236 | KEEP AS NON CORE | Summary: Cytosol (Reactome), from the PEX5:cargo docking-complex step. Correct pre-import location; non-core. Redundant with the other cytosol annotation. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | 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. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-192341 | ACCEPT | 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. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-193533 | ACCEPT | Summary: Peroxisomal matrix (Reactome), same accurate compartment. Redundant with the other peroxisomal matrix annotations; core. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-390224 | ACCEPT | Summary: Peroxisomal matrix (Reactome), from the 3-ketopristanoyl-CoA thiolysis step. Accurate core compartment; redundant. |
| GO:0000062 fatty-acyl-CoA binding | IDA PMID:18465878 Structure and function of the sterol carrier protein-2 N-ter... | KEEP AS NON CORE | 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). |
| GO:0070538 oleic acid binding | IDA PMID:18465878 Structure and function of the sterol carrier protein-2 N-ter... | KEEP AS NON CORE | 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. |
| GO:0015485 cholesterol binding | IDA PMID:18465878 Structure and function of the sterol carrier protein-2 N-ter... | KEEP AS 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. |
| GO:1901373 lipid hydroperoxide transport | IDA PMID:15449949 Sterol carrier protein-2-facilitated intermembrane transfer ... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:15449949 SCP-2 accelerates 7alpha-OOH transfer from SUVs to isolated mitochondria |
| GO:0032385 positive regulation of intracellular cholesterol transport | IDA PMID:15449949 Sterol carrier protein-2-facilitated intermembrane transfer ... | KEEP AS 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. Supporting Evidence: PMID:15449949 Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid (PL) transfer/exchange between membranes |
| GO:0036042 long-chain fatty acyl-CoA binding | IDA PMID:17418802 Investigation of the ligand spectrum of human sterol carrier... | KEEP 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. Supporting Evidence: PMID:17418802 The observation that LCFA-CoAs are high affinity ligands for SCP2 was confirmed, while LCFA-carnitines were demonstrated for the first time not to interact with SCP2 |
| GO:0032991 protein-containing complex | IDA PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe... | MARK AS OVER ANNOTATED | 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. |
| GO:0005102 signaling receptor binding | IPI PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein... | MARK AS 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). Marked over-annotated. Supporting Evidence: PMID:21375735 receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely dependent on the presence of the PTS1 |
| GO:0005515 protein binding | IPI PMID:19584060 Solution structure of human Pex5.Pex14.PTS1 protein complexe... | MARK AS OVER ANNOTATED | 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; over-annotated. |
| GO:0005777 peroxisome | IDA PMID:21375735 The Peroxisomal Targeting Signal 1 in sterol carrier protein... | ACCEPT | Summary: Peroxisome by direct assay (GFP-SCP2 import into peroxisomes in fibroblast complementation). Strong direct support for the core peroxisomal localization. Supporting Evidence: PMID:21375735 receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely dependent on the presence of the PTS1 |
| GO:0005777 peroxisome | IDA PMID:1347505 Subcellular localisation and processing of non-specific lipi... | ACCEPT | Summary: Peroxisome by direct assay (immunoblotting + subcellular fractionation localizing nsLTP to peroxisomes). Direct support for the core peroxisomal localization. Supporting Evidence: PMID:1347505 non-specific lipid transfer protein (nsLTP), another peroxisomal protein synthesised as a larger precursor, is localised in peroxisomes |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-2066781 | ACCEPT | Summary: Peroxisomal matrix (Reactome), from the DHA-CoA formation step catalyzed by SCPx. Accurate core compartment; redundant. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-9033235 | ACCEPT | Summary: Peroxisomal matrix (Reactome), the destination of PEX5 cargo translocation. Accurate core compartment; redundant with other peroxisomal matrix annotations. |
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