SCP2

UniProt ID: P22307
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

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.

Existing Annotations Review

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.

Core Functions

Peroxisomal branched-chain 3-ketoacyl-CoA (3-oxopristanoyl-CoA) thiolase: the SCPx thiolase domain catalyzes the thiolytic-cleavage (last) step of peroxisomal beta-oxidation for 2-methyl branched-chain fatty acyl-CoAs (pristanate) and the C27 bile-acid intermediates DHCA/THCA, activities the conventional peroxisomal thiolase performs poorly.

Molecular Function:
propionyl-CoA C2-trimethyltridecanoyltransferase activity
Directly Involved In:
fatty acid beta-oxidation bile acid biosynthetic process
Cellular Locations:
peroxisomal matrix
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
  • PMID:16685654
    the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids

Intracellular sterol/lipid transfer: the SCP2 (nonspecific lipid-transfer protein) domain removes cholesterol from a donor membrane, shields it in a hydrophobic pocket, and delivers it to an acceptor membrane, facilitating intermembrane cholesterol and phospholipid trafficking in the cytosol and at the endoplasmic reticulum.

Molecular Function:
cholesterol transfer activity
Directly Involved In:
sterol transport
Cellular Locations:
cytosol endoplasmic reticulum
Supporting Evidence:
  • PMID:15449949
    Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid (PL) transfer/exchange between membranes and appears to play a key role in intracellular lipid trafficking
  • PMID:15182174
    Since sterol carrier protein-2 (SCP-2) binds both cholesterol and phosphatidylinositol

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10706581
Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method.
  • SCPx plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids; a specific assay measuring choloyl-CoA production from a bile-acid intermediate was developed and shown deficient in SCPx-knockout mouse fibroblasts.
    "Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids."
PMID:11734571
Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid.
  • Both the conventional 3-ketoacyl-CoA thiolase and SCPx are among the main peroxisomal enzymes catalyzing beta-oxidation of C24:6n-3 to DHA (C22:6n-3).
    "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"
PMID:1347505
Subcellular localisation and processing of non-specific lipid transfer protein are not aberrant in Rhizomelic Chondrodysplasia Punctata fibroblasts.
  • nsLTP (the SCP2 product) is localised to peroxisomes and present as its mature processed form, even in RCDP fibroblasts.
    "non-specific lipid transfer protein (nsLTP), another peroxisomal protein synthesised as a larger precursor, is localised in peroxisomes and is present as the mature protein in RCDP fibroblasts"
PMID:15182174
Sterol carrier protein-2 directly interacts with caveolin-1 in vitro and in vivo.
  • SCP-2 binds both cholesterol and phosphatidylinositol and directly interacts with caveolin-1, implicating it in trafficking these lipids to caveolae/lipid rafts.
    "SCP-2 (but not PITP) selectively interacted with caveolin-1, both within the cytoplasm and at the plasma membrane"
PMID:15449949
Sterol carrier protein-2-facilitated intermembrane transfer of cholesterol- and phospholipid-derived hydroperoxides.
  • SCP-2 facilitates intermembrane transfer/exchange of cholesterol and phospholipids and can also traffic their hydroperoxide (LOOH) derivatives, accelerating peroxidative damage.
    "Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid (PL) transfer/exchange between membranes and appears to play a key role in intracellular lipid trafficking"
PMID:16685654
Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.
  • The first SCPx-deficient patient shows leukoencephalopathy with dystonia and motor neuropathy, pristanic-acid accumulation and abnormal bile-alcohol glucuronides; fibroblasts lack SCPx thiolytic activity and SCPx protein.
    "In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting"
PMID:17157249
Recognition of a functional peroxisome type 1 target by the dynamic import receptor pex5p.
  • The SCP2 gene yields two products (58 kDa SCPx thiolase-SCP2 fusion, and ~15 kDa preSCP2 processed to mature SCP2); SCP2 is a folded PTS1 cargo recognized by PEX5, and its lipid binding is retained when receptor-bound.
    "The SCP2 gene is translated into two protein products: SCPx, a 58 kDa fusion protein comprising an N-terminal thiolase domain and a C-terminal SCP2 domain, and preSCP2, a protein with a molecular mass of about 15 kDa"
PMID:17418802
Investigation of the ligand spectrum of human sterol carrier protein 2 using a direct mass spectrometry assay.
  • Native mass spectrometry confirmed that long-chain fatty acyl-CoAs are high-affinity SCP2 ligands, whereas the equivalent LCFA-carnitines do not bind.
    "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"
PMID:18465878
Structure and function of the sterol carrier protein-2 N-terminal presequence.
  • The 20-residue N-terminal presequence of proSCP-2 modulates SCP-2 structure, cholesterol localization in the ligand-binding site, membrane association and intracellular targeting; SCP-2 binds cholesterol and fatty acyl-CoAs.
    "membrane association, and, potentially, intracellular targeting"
PMID:19584060
Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by small angle X-ray scattering.
  • SAXS/SLS analysis of the human PEX5.PEX14 complex loaded with SCP2 (PTS1 cargo); SCP2 is a transient cargo within the peroxisomal import machinery, not a stable functional complex partner.
    "the interaction of the cargo-loaded Pex5p receptor and the peroxisomal membrane protein Pex14p is the essential primary docking step"
PMID:19946888
Defining the membrane proteome of NK cells.
  • Large-scale mass-spectrometry survey of the NK-cell (YTS) membrane proteome that incidentally identified SCP2 among ~1843 proteins.
    "identified 1843 proteins with high confidence scores"
PMID:21375735
The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition.
  • SCP2 import into peroxisomes is absolutely dependent on its C-terminal PTS1; the ancillary secondary Pex5p interface is dispensable for import.
    "receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely dependent on the presence of the PTS1"
PMID:21516116
Next-generation sequencing to generate interactome datasets.
  • A next-generation-sequencing yeast-two-hybrid interactome-mapping pipeline (Stitch-seq) that generated a human binary interactome dataset including an SCP2 interaction.
    "used it to generate a new human"
PMID:25416956
A proteome-scale map of the human interactome network.
  • A systematic proteome-scale map of ~14,000 high-quality human binary protein-protein interactions, one of which involves SCP2.
    "we describe a systematic map of ?14,000 high-quality human"
PMID:9245689
Sterol carrier protein X (SCPx) is a peroxisomal branched-chain beta-ketothiolase specifically reacting with 3-oxo-pristanoyl-CoA: a new, unique role for SCPx in branched-chain fatty acid metabolism in peroxisomes.
  • SCPx is the peroxisomal branched-chain beta-ketothiolase that readily cleaves 3-oxopristanoyl-CoA, a reaction the conventional peroxisomal thiolase performs poorly; SCPx is thus central to branched-chain fatty acid beta-oxidation.
    "SCPx, a 58 kDa protein with both thiolase and sterol carrier protein activity but unknown function so far, readily reacts with 3-oxopristanoyl-CoA"
Reactome:R-HSA-192341
Thiolysis of 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA yields choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA
Reactome:R-HSA-193368
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
Reactome:R-HSA-193533
Thiolysis of 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA yields chenodeoxycholoyl-CoA (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA
Reactome:R-HSA-2046106
alpha-linolenic acid (ALA) metabolism
Reactome:R-HSA-2066781
Formation of DHA-CoA catalysed by sterol carrier protein X (SCPx)
Reactome:R-HSA-389887
Beta-oxidation of pristanoyl-CoA
Reactome:R-HSA-390224
3-ketopristanoyl-CoA + CoASH => 4,8,12-trimethyltridecanoyl-CoA + propionyl-CoA
Reactome:R-HSA-9033235
Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
Reactome:R-HSA-9033236
PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation Module)

📚 Additional Documentation

Notes

(SCP2-notes.md)

SCP2 (human) — curation notes

UniProt: P22307 (SCP2_HUMAN). HGNC:10606. Gene SCP2 on chromosome 1.

Bifunctional gene / two protein products

The SCP2 gene encodes two protein products from alternative promoter usage /
processing, sharing a common C-terminal SCP2 (sterol-carrier) domain:

  • SCPx (SCP-x, 58 kDa; isoform P22307-1): an N-terminal thiolase domain
    fused to a C-terminal SCP2 domain. It is a peroxisomal 3-ketoacyl-CoA
    thiolase     specialized for branched-chain (2-methyl) fatty acids and the
    bile-acid C27 intermediates (DHCA/THCA) — substrates the conventional
    peroxisomal thiolase (ACAA1) handles poorly.
    PMID:17157249

  • SCP2 (nonspecific lipid-transfer protein, nsLTP, ~13 kDa mature; isoform
    P22307-2)    : the C-terminal SCP2 domain alone, an intracellular
    sterol/phospholipid/fatty-acyl-CoA carrier. Made as preSCP2 (~15 kDa) and
    processed by cleavage of a 20-residue leader after peroxisomal import
    [file:human/SCP2/SCP2-uniprot.txt "preSCP2, a protein with a molecular mass of about 15 kDa, is processed into its mature form (SCP2) by proteolytic cleavage of a 20 residue leader sequence after translocation into peroxisomes"].

The displayed sequence in P22307 is the 547-aa SCPx form; the SCP2 domain is
residues ~433–543 (FT DOMAIN 433..543).

Thiolase / branched-chain and bile-acid beta-oxidation (SCPx)

  • SCPx is the branched-chain beta-ketothiolase that specifically cleaves
    3-oxopristanoyl-CoA — a role the conventional thiolase cannot fulfil.
    PMID:9245689;
    PMID:9245689;
    PMID:9245689.
  • SCPx catalyzes the last (thiolytic) step of peroxisomal beta-oxidation of
    branched-chain fatty acids and of the bile-acid intermediates DHCA and THCA.
    PMID:10706581;
    UniProt FUNCTION [Isoform SCPx]:
    [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)"].
  • The specific thiolytic reaction (choloyl-CoA + propanoyl-CoA ⇌
    trihydroxy-oxo-cholestanoyl-CoA + CoA; EC 2.3.1.176) is the bile-acid step;
    the trimethyltridecanoyl/propanoyl reaction (RHEA:10408) is the pristanate step
    (GO:0050632). [file:human/SCP2/SCP2-uniprot.txt catalytic-activity blocks].
  • SCPx (with the conventional thiolase) also participates in beta-oxidation of
    C24:6n-3 during DHA synthesis.
    PMID:11734571.

Disease (SCPx / SCP2 deficiency = LKDMN, MIM 613724)

  • First patient: torticollis, dystonic head tremor, cerebellar signs,
    leukencephalopathy, azoospermia; plasma pristanic-acid accumulation and
    abnormal bile-alcohol glucuronides in urine; thiolytic SCPx activity deficient
    and no SCPx protein by western blot; homozygous frameshift.
    PMID:16685654;
    PMID:16685654;
    PMID:16685654.

Lipid-transfer / sterol-carrier function (SCP2 domain)

  • SCP-2 transfers cholesterol and phospholipids between membranes; role in
    intracellular lipid trafficking.
    PMID:15449949.
  • It can also traffic cholesterol- and phospholipid-derived hydroperoxides
    (LOOH), accelerating dissemination of peroxidative damage and promoting loss of
    mitochondrial membrane potential.
    PMID:15449949.
  • SCP-2 binds cholesterol and phosphatidylinositol; the N-terminal presequence
    modulates ligand binding and targeting.
    PMID:15182174;
    cross-linking by photoactivatable free cholesterol and a mitochondrial
    presequence are described in PMID:18465878.
  • Direct high-affinity ligands include long-chain fatty acyl-CoAs (not the
    carnitine esters). PMID:17418802.
  • SCP2 directly interacts with caveolin-1, implicated in trafficking cholesterol
    and PI to caveolae/rafts.
    PMID:15182174.
  • ER→PM cholesterol transfer role in fibroblasts; reduced in patient fibroblasts
    (UniProt FUNCTION [Isoform SCP2], PubMed:7642518, not cached here beyond
    UniProt).

Localization / peroxisomal import

  • SCP2 is a bona fide peroxisomal matrix protein (PTS1 = C-terminal -AKL), imported
    by PEX5; import is strictly PTS1-dependent.
    PMID:21375735;
    the SCP2/PEX5 co-crystal is the model PTS1 receptor–cargo structure
    [PMID:17157249 crystal structure of Pex5p(C) with mSCP2].
  • nsLTP is correctly localized to peroxisomes and processed to mature form even in
    RCDP fibroblasts.
    PMID:1347505.
  • UniProt also records SCP2 (transfer form) in cytoplasm, ER and (weakly)
    mitochondrion; SCPx is peroxisome only.

Notes on annotation actions

  • Core MFs: GO:0050632 (propionyl-CoA C2-trimethyltridecanoyltransferase =
    branched-chain 3-oxopristanoyl-CoA thiolase; has EXP support PMID:9245689,
    16685654, 11734571) and GO:0120020 (cholesterol transfer activity, IMP).
    GO:0003988 / GO:0050633 are more-general or in-vitro chain-length variants of
    the same thiolase activity (ISS/IEA) — kept but non-core.
  • Core BPs: fatty acid beta-oxidation (GO:0006635), bile acid biosynthetic /
    metabolic process, intracellular cholesterol transport / sterol transport.
  • Bare "protein binding" IPIs (GO:0005515) and high-throughput interactome hits
    are marked over-annotated (not informative); the caveolin-1 and PEX5-related
    interactions are real but better captured elsewhere.
  • Mass-spec "membrane" (HDA, NK-cell membrane proteome) and mitochondrion IEA/ISS
    are non-core / likely over-annotations for a peroxisomal matrix + cytosolic
    lipid-transfer protein.

📄 View Raw YAML

 
id: P22307
gene_symbol: SCP2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: SCPx {ECO:0000303|PubMed:17157249}
  id: P22307-1
- name: SCP2 {ECO:0000303|PubMed:17157249}
  id: P22307-2
  sequence_note: VSP_018977
- name: '3'
  id: P22307-3
  sequence_note: VSP_042686, VSP_042687
- name: '4'
  id: P22307-4
  sequence_note: VSP_045187
- name: '5'
  id: P22307-5
  sequence_note: VSP_018977, VSP_047269, VSP_047270
- name: '6'
  id: P22307-6
  sequence_note: VSP_018977, VSP_047268
- name: '7'
  id: P22307-7
  sequence_note: VSP_042686
- name: '8'
  id: P22307-8
  sequence_note: VSP_047267
existing_annotations:
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:1347505
      supporting_text: >-
        non-specific lipid transfer protein (nsLTP), another peroxisomal protein
        synthesised as a larger precursor, is localised in peroxisomes
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:9245689
      supporting_text: >-
        SCPx, a 58 kDa protein with both thiolase and sterol carrier protein
        activity but unknown function so far, readily reacts with 3-oxopristanoyl-CoA
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Peroxisome from subcellular-location mapping. Consistent with the core
      localization; redundant with the IDA/IBA/ISS peroxisome annotations.
    action: ACCEPT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/SCP2/SCP2-uniprot.txt
      supporting_text: >-
        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)
- term:
    id: GO:0015918
    label: sterol transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Sterol transport (ARBA). Consistent with the SCP2 domain's role as a
      sterol/cholesterol carrier; correct process for the transfer function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15449949
      supporting_text: >-
        Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and
        phospholipid (PL) transfer/exchange between membranes
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0016747
    label: acyltransferase activity, transferring groups other than amino-acyl groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      General acyltransferase (non-amino-acyl) activity from InterPro thiolase
      signatures. Correct but uninformative parent term; superseded by the specific
      thiolase MF.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0019216
    label: regulation of lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0019395
    label: fatty acid oxidation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0033814
    label: propanoyl-CoA C-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10706581
      supporting_text: >-
        Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal
        oxidation of branched-chain fatty acids
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9245689
      supporting_text: >-
        SCPx, a 58 kDa protein with both thiolase and sterol carrier protein
        activity but unknown function so far, readily reacts with 3-oxopristanoyl-CoA
- term:
    id: GO:0050633
    label: acetyl-CoA C-myristoyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15182174
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:15182174
      supporting_text: >-
        SCP-2 (but not PITP) selectively interacted with caveolin-1, both within the
        cytoplasm and at the plasma membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a proteome-scale binary interactome map (partner
      TRIP13/Q15645). Uninformative high-throughput interaction; marked
      over-annotated.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193368
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SCP2/SCP2-uniprot.txt
      supporting_text: >-
        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)
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-389887
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:9245689
      supporting_text: >-
        SCPx plays a central role in branched chain fatty acid beta-oxidation in
        peroxisomes
- term:
    id: GO:0036109
    label: alpha-linolenic acid metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2046106
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:11734571
      supporting_text: >-
        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
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Peroxisome by immunofluorescence (HPA). Directly supports the core peroxisomal
      localization.
    action: ACCEPT
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:10706581
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:17157249
  qualifier: located_in
  review:
    summary: >-
      Experimental cytoplasm localization (SCP2). Newly synthesized SCP2/preSCP2
      resides in the cytosol before PTS1/PEX5-dependent peroxisomal import. Correct;
      non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Mitochondrion by similarity (rat P32020). Only a minor mitochondrial pool is
      reported (SCP2 has a putative mitochondrial presequence); not a core site.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:17157249
  qualifier: located_in
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Peroxisome by similarity (rat P11915). Redundant support for the core
      peroxisomal localization.
    action: ACCEPT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ER by similarity (rat P32020). Consistent with the transfer protein acting at
      the ER in lipid trafficking; non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Branched-chain 3-oxopristanoyl-CoA thiolase activity by similarity (rat
      P11915). Core molecular function; redundant with the EXP annotations for this
      term.
    action: ACCEPT
- term:
    id: GO:0050633
    label: acetyl-CoA C-myristoyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Acetyl-CoA C-myristoyltransferase by similarity. A straight-chain thiolase
      variant of the general activity, not the distinctive branched-chain role;
      non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:11734571
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11734571
      supporting_text: >-
        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
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:16685654
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16685654
      supporting_text: >-
        In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient,
        and no SCPx protein could be detected by western blotting
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:9245689
  qualifier: enables
  review:
    summary: >-
      Foundational experimental demonstration that SCPx is the branched-chain
      beta-ketothiolase specifically reacting with 3-oxopristanoyl-CoA. Core
      molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9245689
      supporting_text: >-
        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
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192341
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for the SCPx-catalyzed thiolytic step (trihydroxy-cholestanoyl
      thiolysis to choloyl-CoA + propionyl-CoA). Supports the core thiolase MF.
    action: ACCEPT
- term:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193533
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for the analogous SCPx thiolytic step in chenodeoxycholoyl-CoA
      formation. Supports the core thiolase MF.
    action: ACCEPT
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Fatty acid beta-oxidation by similarity. SCPx catalyzes the thiolytic step of
      peroxisomal beta-oxidation; a core biological process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9245689
      supporting_text: >-
        SCPx plays a central role in branched chain fatty acid beta-oxidation in
        peroxisomes
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: >-
      Cytosol (Reactome) — the compartment from which PEX5 cargo (including SCP2)
      translocates into the peroxisomal matrix. Correct pre-import location;
      non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  qualifier: located_in
  review:
    summary: >-
      Cytosol (Reactome), from the PEX5:cargo docking-complex step. Correct
      pre-import location; non-core. Redundant with the other cytosol annotation.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192341
  qualifier: located_in
  review:
    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.
    action: ACCEPT
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193533
  qualifier: located_in
  review:
    summary: >-
      Peroxisomal matrix (Reactome), same accurate compartment. Redundant with the
      other peroxisomal matrix annotations; core.
    action: ACCEPT
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390224
  qualifier: located_in
  review:
    summary: >-
      Peroxisomal matrix (Reactome), from the 3-ketopristanoyl-CoA thiolysis step.
      Accurate core compartment; redundant.
    action: ACCEPT
- term:
    id: GO:0000062
    label: fatty-acyl-CoA binding
  evidence_type: IDA
  original_reference_id: PMID:18465878
  qualifier: enables
  review:
    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).
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0070538
    label: oleic acid binding
  evidence_type: IDA
  original_reference_id: PMID:18465878
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0015485
    label: cholesterol binding
  evidence_type: IDA
  original_reference_id: PMID:18465878
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:1901373
    label: lipid hydroperoxide transport
  evidence_type: IDA
  original_reference_id: PMID:15449949
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:15449949
      supporting_text: >-
        SCP-2 accelerates 7alpha-OOH transfer from SUVs to isolated mitochondria
- term:
    id: GO:0032385
    label: positive regulation of intracellular cholesterol transport
  evidence_type: IDA
  original_reference_id: PMID:15449949
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:15449949
      supporting_text: >-
        Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and
        phospholipid (PL) transfer/exchange between membranes
- term:
    id: GO:0036042
    label: long-chain fatty acyl-CoA binding
  evidence_type: IDA
  original_reference_id: PMID:17418802
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17418802
      supporting_text: >-
        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
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19584060
  qualifier: part_of
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:21375735
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:21375735
      supporting_text: >-
        receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely
        dependent on the presence of the PTS1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19584060
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:21375735
  qualifier: located_in
  review:
    summary: >-
      Peroxisome by direct assay (GFP-SCP2 import into peroxisomes in fibroblast
      complementation). Strong direct support for the core peroxisomal localization.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:21375735
      supporting_text: >-
        receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely
        dependent on the presence of the PTS1
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:1347505
  qualifier: located_in
  review:
    summary: >-
      Peroxisome by direct assay (immunoblotting + subcellular fractionation
      localizing nsLTP to peroxisomes). Direct support for the core peroxisomal
      localization.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:1347505
      supporting_text: >-
        non-specific lipid transfer protein (nsLTP), another peroxisomal protein
        synthesised as a larger precursor, is localised in peroxisomes
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2066781
  qualifier: located_in
  review:
    summary: >-
      Peroxisomal matrix (Reactome), from the DHA-CoA formation step catalyzed by
      SCPx. Accurate core compartment; redundant.
    action: ACCEPT
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: >-
      Peroxisomal matrix (Reactome), the destination of PEX5 cargo translocation.
      Accurate core compartment; redundant with other peroxisomal matrix
      annotations.
    action: ACCEPT
core_functions:
- description: >-
    Peroxisomal branched-chain 3-ketoacyl-CoA (3-oxopristanoyl-CoA) thiolase: the
    SCPx thiolase domain catalyzes the thiolytic-cleavage (last) step of
    peroxisomal beta-oxidation for 2-methyl branched-chain fatty acyl-CoAs
    (pristanate) and the C27 bile-acid intermediates DHCA/THCA, activities the
    conventional peroxisomal thiolase performs poorly.
  molecular_function:
    id: GO:0050632
    label: propionyl-CoA C2-trimethyltridecanoyltransferase activity
  directly_involved_in:
  - id: GO:0006635
    label: fatty acid beta-oxidation
  - id: GO:0006699
    label: bile acid biosynthetic process
  locations:
  - id: GO:0005782
    label: peroxisomal matrix
  supported_by:
  - reference_id: PMID:9245689
    supporting_text: >-
      SCPx, a 58 kDa protein with both thiolase and sterol carrier protein activity
      but unknown function so far, readily reacts with 3-oxopristanoyl-CoA
  - reference_id: PMID:16685654
    supporting_text: >-
      the first known patient with a deficiency of sterol carrier protein X (SCPx),
      a peroxisomal enzyme with thiolase activity, which is required for the
      breakdown of branched-chain fatty acids
- description: >-
    Intracellular sterol/lipid transfer: the SCP2 (nonspecific lipid-transfer
    protein) domain removes cholesterol from a donor membrane, shields it in a
    hydrophobic pocket, and delivers it to an acceptor membrane, facilitating
    intermembrane cholesterol and phospholipid trafficking in the cytosol and at
    the endoplasmic reticulum.
  molecular_function:
    id: GO:0120020
    label: cholesterol transfer activity
  directly_involved_in:
  - id: GO:0015918
    label: sterol transport
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: PMID:15449949
    supporting_text: >-
      Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid
      (PL) transfer/exchange between membranes and appears to play a key role in
      intracellular lipid trafficking
  - reference_id: PMID:15182174
    supporting_text: >-
      Since sterol carrier protein-2 (SCP-2) binds both cholesterol and
      phosphatidylinositol
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10706581
  title: Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein
    X (SCPx). Activity measurements in liver and fibroblasts using a newly developed
    method.
  findings:
  - statement: >-
      SCPx plays a crucial role in the peroxisomal oxidation of branched-chain fatty
      acids; a specific assay measuring choloyl-CoA production from a bile-acid
      intermediate was developed and shown deficient in SCPx-knockout mouse
      fibroblasts.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal
      oxidation of branched-chain fatty acids.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; establishes SCPx's role in branched-chain fatty acid oxidation
      and the specific bile-acid thiolase assay. PubMed-verified.
- id: PMID:11734571
  title: Identification of the peroxisomal beta-oxidation enzymes involved in the
    biosynthesis of docosahexaenoic acid.
  findings:
  - statement: >-
      Both the conventional 3-ketoacyl-CoA thiolase and SCPx are among the main
      peroxisomal enzymes catalyzing beta-oxidation of C24:6n-3 to DHA (C22:6n-3).
    reference_section_type: ABSTRACT
    supporting_text: >-
      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
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; supports SCPx participation in peroxisomal beta-oxidation during
      DHA synthesis (ALA metabolism annotation). PubMed-verified.
- id: PMID:1347505
  title: Subcellular localisation and processing of non-specific lipid transfer protein
    are not aberrant in Rhizomelic Chondrodysplasia Punctata fibroblasts.
  findings:
  - statement: >-
      nsLTP (the SCP2 product) is localised to peroxisomes and present as its mature
      processed form, even in RCDP fibroblasts.
    reference_section_type: ABSTRACT
    supporting_text: >-
      non-specific lipid transfer protein (nsLTP), another peroxisomal protein
      synthesised as a larger precursor, is localised in peroxisomes and is present
      as the mature protein in RCDP fibroblasts
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; direct evidence for peroxisomal localization and precursor
      processing of nsLTP/SCP2. PubMed-verified.
- id: PMID:15182174
  title: Sterol carrier protein-2 directly interacts with caveolin-1 in vitro and
    in vivo.
  findings:
  - statement: >-
      SCP-2 binds both cholesterol and phosphatidylinositol and directly interacts
      with caveolin-1, implicating it in trafficking these lipids to caveolae/lipid
      rafts.
    reference_section_type: ABSTRACT
    supporting_text: >-
      SCP-2 (but not PITP) selectively interacted with caveolin-1, both within the
      cytoplasm and at the plasma membrane
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; supports cholesterol/PI binding and the caveolin-1 interaction
      (basis of two IPI protein binding annotations). PubMed-verified.
- id: PMID:15449949
  title: Sterol carrier protein-2-facilitated intermembrane transfer of cholesterol-
    and phospholipid-derived hydroperoxides.
  findings:
  - statement: >-
      SCP-2 facilitates intermembrane transfer/exchange of cholesterol and
      phospholipids and can also traffic their hydroperoxide (LOOH) derivatives,
      accelerating peroxidative damage.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Sterol carrier protein-2 (SCP-2) facilitates cholesterol (Ch) and phospholipid
      (PL) transfer/exchange between membranes and appears to play a key role in
      intracellular lipid trafficking
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; primary support for the sterol/phospholipid transfer activity
      and the lipid-hydroperoxide-transport / cholesterol-transport-regulation
      annotations. PubMed-verified.
- id: PMID:16685654
  title: Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx)
    cause leukencephalopathy with dystonia and motor neuropathy.
  findings:
  - statement: >-
      The first SCPx-deficient patient shows leukoencephalopathy with dystonia and
      motor neuropathy, pristanic-acid accumulation and abnormal bile-alcohol
      glucuronides; fibroblasts lack SCPx thiolytic activity and SCPx protein.
    reference_section_type: ABSTRACT
    supporting_text: >-
      In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient,
      and no SCPx protein could be detected by western blotting
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text (abstract identical) available; disease-defining loss-of-function
      evidence for the SCPx thiolase and the LKDMN phenotype. PubMed-verified.
- id: PMID:17157249
  title: Recognition of a functional peroxisome type 1 target by the dynamic import
    receptor pex5p.
  findings:
  - statement: >-
      The SCP2 gene yields two products (58 kDa SCPx thiolase-SCP2 fusion, and ~15
      kDa preSCP2 processed to mature SCP2); SCP2 is a folded PTS1 cargo recognized
      by PEX5, and its lipid binding is retained when receptor-bound.
    reference_section_type: RESULTS
    supporting_text: >-
      The SCP2 gene is translated into two protein products: SCPx, a 58 kDa fusion
      protein comprising an N-terminal thiolase domain and a C-terminal SCP2 domain,
      and preSCP2, a protein with a molecular mass of about 15 kDa
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; source of the two-product bifunctional gene model and the
      PEX5/PTS1 import mechanism; supports cytoplasm/mitochondrion localization
      annotations. PubMed-verified.
- id: PMID:17418802
  title: Investigation of the ligand spectrum of human sterol carrier protein 2 using
    a direct mass spectrometry assay.
  findings:
  - statement: >-
      Native mass spectrometry confirmed that long-chain fatty acyl-CoAs are
      high-affinity SCP2 ligands, whereas the equivalent LCFA-carnitines do not bind.
    reference_section_type: ABSTRACT
    supporting_text: >-
      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
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; direct support for long-chain fatty-acyl-CoA binding (IDA).
      PubMed-verified.
- id: PMID:18465878
  title: Structure and function of the sterol carrier protein-2 N-terminal presequence.
  findings:
  - statement: >-
      The 20-residue N-terminal presequence of proSCP-2 modulates SCP-2 structure,
      cholesterol localization in the ligand-binding site, membrane association and
      intracellular targeting; SCP-2 binds cholesterol and fatty acyl-CoAs.
    reference_section_type: ABSTRACT
    supporting_text: >-
      membrane association, and, potentially, intracellular targeting
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; basis for cholesterol binding, fatty-acyl-CoA binding and oleic
      acid binding IDAs, and for the mitochondrial/peroxisomal targeting behavior.
      PubMed-verified.
- id: PMID:19584060
  title: Solution structure of human Pex5.Pex14.PTS1 protein complexes obtained by
    small angle X-ray scattering.
  findings:
  - statement: >-
      SAXS/SLS analysis of the human PEX5.PEX14 complex loaded with SCP2 (PTS1
      cargo); SCP2 is a transient cargo within the peroxisomal import machinery, not
      a stable functional complex partner.
    reference_section_type: ABSTRACT
    supporting_text: >-
      the interaction of the cargo-loaded Pex5p receptor and the peroxisomal membrane
      protein Pex14p is the essential primary docking step
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available; basis of the protein-containing-complex (IDA) and a PEX5
      protein-binding (IPI) annotation; the interaction is import-machinery cargo
      loading, not a core functional complex. PubMed-verified.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: >-
      Large-scale mass-spectrometry survey of the NK-cell (YTS) membrane proteome
      that incidentally identified SCP2 among ~1843 proteins.
    reference_section_type: ABSTRACT
    supporting_text: >-
      identified 1843 proteins with high confidence scores
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; high-throughput proteomics source of the generic membrane (HDA)
      annotation; not specific to SCP2 function. PubMed-verified.
- id: PMID:21375735
  title: The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous
    and essential for receptor recognition.
  findings:
  - statement: >-
      SCP2 import into peroxisomes is absolutely dependent on its C-terminal PTS1;
      the ancillary secondary Pex5p interface is dispensable for import.
    reference_section_type: ABSTRACT
    supporting_text: >-
      receptor-cargo binding and SCP2 transfer into the peroxisome are absolutely
      dependent on the presence of the PTS1
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; direct peroxisomal-import evidence (IDA peroxisome) and
      the PEX5 interaction annotated as signaling receptor binding (mischaracterized
      MF). PubMed-verified.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings:
  - statement: >-
      A next-generation-sequencing yeast-two-hybrid interactome-mapping pipeline
      (Stitch-seq) that generated a human binary interactome dataset including an
      SCP2 interaction.
    reference_section_type: ABSTRACT
    supporting_text: >-
      used it to generate a new human
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available; high-throughput binary-interaction source for a bare
      protein-binding IPI (TRIP13). Method paper, not SCP2-specific. PubMed-verified.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: >-
      A systematic proteome-scale map of ~14,000 high-quality human binary
      protein-protein interactions, one of which involves SCP2.
    reference_section_type: ABSTRACT
    supporting_text: >-
      we describe a systematic map of ?14,000 high-quality human
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available; high-throughput interactome source for a bare
      protein-binding IPI (TRIP13). Not SCP2-specific. PubMed-verified.
- id: PMID:9245689
  title: 'Sterol carrier protein X (SCPx) is a peroxisomal branched-chain beta-ketothiolase
    specifically reacting with 3-oxo-pristanoyl-CoA: a new, unique role for SCPx in
    branched-chain fatty acid metabolism in peroxisomes.'
  findings:
  - statement: >-
      SCPx is the peroxisomal branched-chain beta-ketothiolase that readily cleaves
      3-oxopristanoyl-CoA, a reaction the conventional peroxisomal thiolase performs
      poorly; SCPx is thus central to branched-chain fatty acid beta-oxidation.
    reference_section_type: ABSTRACT
    supporting_text: >-
      SCPx, a 58 kDa protein with both thiolase and sterol carrier protein activity
      but unknown function so far, readily reacts with 3-oxopristanoyl-CoA
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only; foundational identification of the SCPx branched-chain thiolase
      activity (core MF). PubMed-verified.
- id: Reactome:R-HSA-192341
  title: Thiolysis of 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA yields
    choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) and propionyl
    CoA
  findings: []
- id: Reactome:R-HSA-193368
  title: Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193533
  title: Thiolysis of 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA yields chenodeoxycholoyl-CoA
    (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA
  findings: []
- id: Reactome:R-HSA-2046106
  title: alpha-linolenic acid (ALA) metabolism
  findings: []
- id: Reactome:R-HSA-2066781
  title: Formation of DHA-CoA catalysed by sterol carrier protein X (SCPx)
  findings: []
- id: Reactome:R-HSA-389887
  title: Beta-oxidation of pristanoyl-CoA
  findings: []
- id: Reactome:R-HSA-390224
  title: 3-ketopristanoyl-CoA + CoASH => 4,8,12-trimethyltridecanoyl-CoA + propionyl-CoA
  findings: []
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation
    Module)
  findings: []