SCAP (Q12770) review notes

Session log

• 2026-10-18: Started review. just deep-research human SCAP --provider falcon attempted once;
  it failed at login ("Exception: Failed to authenticate"; the Edison/Falcon key is not
  authorised). Not retried. No -deep-research-*.md file exists; these notes, UniProt and
  cached publications are the evidence base.
• Fetched extra publications: PMID:8898195, 17428919, 12963821, 16399501, 15260976,
  33446483, 32054686, 27068746. Most are abstract-only in the cache.

Identity and architecture

• SCAP = SREBP cleavage-activating protein, 1279 aa, polytopic ER membrane protein with an
  N-terminal eight-TM membrane domain (containing the sterol-sensing domain, SSD, TM2-6) and a
  C-terminal cytosolic WD40 beta-propeller domain that binds the regulatory domain of SREBPs.
  UniProt: "Belongs to the WD repeat SCAP family." PANTHER PTHR46378 (SF1).
• Cloned by expression cloning from sterol-resistant CHO cells PMID:8898195;
  D443N in the SSD gives sterol resistance PMID:8898195.
• Topology: PMID:23564452

Molecular function

1. Cholesterol binding / sterol sensing (the defining activity).
2. Direct binding by purified membrane domain (hamster Scap): PMID:15260976.
3. Conformational change: PMID:12963821; Loop1 binds Loop7 in the transport-competent state and
   cholesterol disrupts this PMID:27068746.
4. Human Scap-Insig-2 cryo-EM: 25HC sits at the Scap SSD / Insig-2 TM3-4 interface
   PMID:33446483. Oxysterols bind INSIG, cholesterol binds
   SCAP PMID:17428920.
5. GO: GOA carries only sterol binding (GO:0032934; IEA InterPro and ISS from hamster). The more
   specific cholesterol binding (GO:0015485, is_a sterol binding) and sterol sensor activity
   (GO:0032935: "Binding to and responding, e.g. by conformational change, to changes in the
   cellular level of a sterol") both fit SCAP better. Comparator: GO:0032935 is used for SLC38A9
   and OSBPL1A (cholesterol sensors) but not SCAP in any species - an obvious gap for the
   archetypal sterol sensor. Proposed NEW.
6. Escort / ER-export cargo receptor for SREBPs. SCAP binds SREBP via its WD40 domain and, in
   sterol-depleted cells, binds Sec23/Sec24 through the cytosolic MELADL hexapeptide in Loop 6.
7. PMID:15899885
8. PMID:17428919.
9. PMID:12242332.
10. GO has no "SREBP escort" term. cargo receptor activity (GO:0038024: "Cargo receptors span
    membranes ... binding simultaneously to cargo molecules and coat adaptors, to efficiently
    recruit the cargo molecules to nascent vesicles") describes exactly this. Comparator:
    carried by other ER-exit COPII cargo receptors (CNIH1/2 IBA, LMAN1, MIA3 IEA). Proposed NEW,
    flagged as a question for experts.
11. Avoid protein binding (three IPI rows: INSIG2, RNF139/TRC8, SPRING1) - REMOVE as uninformative.

Localisation

• ER membrane at steady state (sterol-replete) and Golgi in sterol-depleted cells, with
  COPI-dependent return PMID:32111832; [PMID:26311497 "Scap was mainly co-localized with an ER marker calnexin in
  normal medium"; PAQR3 anchors Scap/SREBP in Golgi]. COPII vesicle membrane (hamster IDA
  PMID:27068746 in GOA; human IEA).

Complexes

• SREBP-SCAP complex (GO:0032936) and SREBP-SCAP-Insig complex (GO:0032937): PMID:12202038; PMID:16399501.
• Membrane domain is a tetramer PMID:15260976.

Processes

• Core: SREBP signaling pathway (GO:0032933), COPII-coated vesicle cargo loading (GO:0090110),
  positive regulation of cholesterol biosynthetic process (GO:0045542).
• cholesterol metabolic process (GO:0008203) rows: SCAP does no metabolic chemistry; it
  regulates synthesis/uptake through SREBP. MODIFY to GO:0045542.
• regulation of transcription by RNA polymerase II (GO:0006357; ComplexPortal-derived): the
  transcriptional output belongs to the SREBP subunit; SCAP acts upstream in ER/Golgi. Marked
  over-annotated (not removed: experimental row, ComplexPortal complex-level inference).
• negative regulation of cholesterol biosynthetic process (NAS, a review on oxysterols):
  sterol-bound SCAP-INSIG is the feedback-inhibition switch, so it is defensible; non-core.
• response to vitamin B3 (rat Ensembl IEA): expression-level response; not a function. REMOVE.

Regulators / partners (context, not annotated as SCAP MF)

• INSIG1/2 (ER anchors), PAQR3 (Golgi anchor; PMID:26311497), RNF139/TRC8
  PMID:19706601, SPRING1
  (Golgi factor needed for SCAP return to ER, PMID:32111832), RNF5 (PMID:32054686, ubiquitination),
  PCK1 phosphorylation of INSIG releases SCAP-SREBP (PMID:32322062), lycorine induces lysosomal
  SCAP degradation (PMID:32432943).

GO-CAM

• The curated human GO-CAM gocams/6205c24300000880 ("Regulation of cholesterol biosynthesis by
  SREBP ... and retention by the SREBP-SCAP complex") has no SCAP (Q12770) activity node; the
  SREBP-SCAP complex appears only as a generic GO:0032936 molecule acted on by INSIG1/2
  (protein sequestering activity, SREBP-SCAP complex retention in endoplasmic reticulum).
  SCAP's own sterol-sensor / escort activity is therefore not modelled. Raised in
  suggested_questions. GO:0036316 (retention) is carried by INSIG1/2 (anchors), not SCAP
  (the retained entity), so not proposed as NEW for SCAP.