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.

2026-11-03 ORGANELLES batch 4 (mitochondrion rows)

Rows: GO:0005739 IEA (GO_REF:0000044, SL-0173), ISS (GO_REF:0000024, WITH UniProtKB:P32020)
and EXP (PMID:17157249), all located_in. No mitochondrial sub-compartment rows.

Checks:
- UniProt P22307: [Isoform SCP2] Mitochondrion tagged ECO:0000269|PubMed:17157249 and
ECO:0000250|UniProtKB:P32020; [Isoform SCPx] peroxisome only.
- PMID:17157249 (Stanley et al. 2006, full text cached incl. Experimental Procedures): the
string "mitochondri" never occurs. Its only cell experiment is GFP fused to mature SCP2
PMID:17157249,
and the leader is described as cleaved in peroxisomes
PMID:17157249.
The earlier summary that this paper describes a mitochondrial transit peptide was wrong.
Recorded as a source defect (WRONG_REFERENCE, UNIPROT, PROBABLE: supplement unseen).
- The ISS donor P32020 is mouse (not rat as the old summary said). UniProt REST (2026-11-03):
P32020 [Isoform SCP2] Mitochondrion {ECO:0000269|PubMed:11003606, PubMed:26901662}.
PMID:26901662 (mouse MA-10 cells, full text cached):
PMID:26901662
PMID:26901662
but the crude 11,000 g fraction was checked for catalase only, not an ER marker, and
PMID:26901662.
QuickGO also lists mouse HDA rows (PMID:14651853, PMID:18614015).
- MitoCarta3.0: SCP2 listed; evidence "Rickettsial homolog, mito protein domain+";
SubMitoLocalization "MIM"; MSMS "50-75crude", 9 tissues; HPA "Peroxisomes (Supported)".

Outcome: all three rows MARK_AS_OVER_ANNOTATED -> KEEP_AS_NON_CORE. The earlier reason
("not a core site") argued non-core, not over-annotation; the minor mitochondrial pool of
isoform SCP2 has mouse fractionation/imaging, mouse proteomes and MitoCarta3.0. The EXP row
keeps the same action because the claim stands on that other evidence, and carries the
source defect. Added PMID:26901662 to references; revised the PMID:17157249 review note.
Stay at the root: MitoCarta's "MIM" is the only sub-mitochondrial line and the presequence
was shown non-functional.

2026-11-05 ORGANELLES ER batch 3 (endoplasmic reticulum rows)

Rows: GO:0005783 IEA (GO_REF:0000044, SL-0095) and ISS (GO_REF:0000024, WITH UniProtKB:P32020),
both located_in, both KEEP_AS_NON_CORE. No ER sub-compartment rows. Mitochondrion rows from
batch 4 untouched.

Checks:
- UniProt P22307: "[Isoform SCP2]: ... Endoplasmic reticulum {ECO:0000250|UniProtKB:P32020}";
"[Isoform SCPx]: Peroxisome" only. So both ER rows rest on mouse P32020.
- UniProt REST P32020 (2026-11-05): [Isoform SCP2] "Endoplasmic reticulum {ECO:0000269|PubMed:11003606}"
(sole source; the 2016 paper PMID:26901662 supports Mitochondrion/Peroxisome/Cytoplasm only,
and only cites earlier ER pools).
- PMID:11003606 (abstract-only, mouse L-cell fibroblasts stably overexpressing SCP-2):
PMID:11003606
plus SCP-2 stimulation of microsomal phosphatidic acid synthesis in vitro.
- Soluble protein, PTS1 -AKL, no signal peptide/TM: any ER pool is on the cytosolic face.

Outcome: actions unchanged (KEEP_AS_NON_CORE), close call against MARK_AS_OVER_ANNOTATED
(overexpression-only localization) stated in the ISS reason. ISS summary corrected (donor is
mouse, not rat). Isoform restriction recorded as a source defect (Gene_Product_Form_ID ->
P22307-2) on the ISS row. Stays at the root. Added PMID:11003606 to references.
core_functions[1] still lists GO:0005783 for the lipid-transfer function; left as is (the
microsomal transfer data are the functional link), but worth a second look.
- Correction (2026-11-06): settled in review of PR #6028. GO:0005783 was removed from the
lipid-transfer core function's locations (cytosol only), and its description now names
donor and acceptor membranes rather than an ER location, since no assay places the transfer
activity at the ER.