SCAP (SREBP cleavage-activating protein) is a polytopic endoplasmic reticulum membrane protein with a sterol-sensing domain and C-terminal WD40 repeats that binds the regulatory domain of the membrane-bound transcription factor SREBP. In the SREBP-SCAP complex it escorts SREBP in COPII vesicles from the ER to the Golgi, where site-1 and site-2 proteases release the N-terminal transcription factor domain. Drosophila cannot synthesize sterols, and in flies SREBP processing is controlled mainly by membrane phospholipid (phosphatidylethanolamine) levels rather than by sterols, so SCAP-dependent SREBP activation regulates fatty acid and phospholipid synthesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: SCAP travels with SREBP in COPII vesicles to the Golgi. Reason: Conserved escort mechanism; appropriate electronic inference for an ER-Golgi cycling protein. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: SCAP is an ER membrane protein. Reason: Polytopic ER membrane protein retaining SREBP in the ER until export; IBA and IEA consistent. |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SCAP is an ER membrane protein. Reason: Polytopic ER membrane protein retaining SREBP in the ER until export; IBA and IEA consistent. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000002 | ACCEPT | Summary: SCAP is an ER membrane protein. Reason: Polytopic ER membrane protein retaining SREBP in the ER until export; IBA and IEA consistent. |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:11988566 Regulation of SREBP processing and membrane lipid production... | KEEP AS NON CORE | Summary: Regulation of RNA Pol II transcription (NAS). Reason: SCAP does not regulate transcription directly; it controls transcription indirectly by escorting SREBP for proteolytic activation. Retained as a non-core, indirect role. |
| GO:0006631 fatty acid metabolic process | NAS PMID:11988566 Regulation of SREBP processing and membrane lipid production... | KEEP AS NON CORE | Summary: Fatty acid metabolic process (NAS), reflecting feedback control of fatty acid synthesis via SREBP. Reason: Downstream metabolic outcome of SREBP activation; SCAP does not act in fatty acid metabolism directly. Supporting Evidence: PMID:11988566 exerting feedback control on the synthesis of fatty acids and phospholipids |
| GO:0012507 ER to Golgi transport vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SCAP travels with SREBP in COPII vesicles to the Golgi. Reason: Conserved escort mechanism; appropriate electronic inference for an ER-Golgi cycling protein. |
| GO:0032933 SREBP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SCAP is required for SREBP activation (SREBP signaling pathway). Reason: Defining role of SCAP; IBA and InterPro inference are consistent with the conserved SREBP-SCAP escort mechanism and with fly SREBP processing data. Supporting Evidence: PMID:11988566 phosphatidylethanolamine, the major phospholipid in Drosophila, controls the release of sterol regulatory element-binding protein (SREBP) from Drosophila cell membranes |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: SCAP is required for SREBP activation (SREBP signaling pathway). Reason: Defining role of SCAP; IBA and InterPro inference are consistent with the conserved SREBP-SCAP escort mechanism and with fly SREBP processing data. Supporting Evidence: PMID:11988566 phosphatidylethanolamine, the major phospholipid in Drosophila, controls the release of sterol regulatory element-binding protein (SREBP) from Drosophila cell membranes |
| GO:0032934 sterol binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Sterol binding inferred from the sterol-sensing domain. Reason: The sterol-sensing domain binds cholesterol in mammalian SCAP, but Drosophila cannot synthesize sterols and fly SREBP processing is regulated by phosphatidylethanolamine rather than sterols. Sterol binding by fly SCAP has not been demonstrated and is not its regulatory input. Supporting Evidence: PMID:11988566 The finding that SREBP processing is controlled by different lipids in mammals and flies (sterols and phosphatidylethanolamine, respectively) |
| GO:0032936 SREBP-SCAP complex | IBA GO_REF:0000033 | ACCEPT | Summary: SCAP forms the SREBP-SCAP complex. Reason: Core complex membership, conserved (IBA) and asserted for the fly proteins by the curators. |
| GO:0032936 SREBP-SCAP complex | NAS PMID:11988566 Regulation of SREBP processing and membrane lipid production... | ACCEPT | Summary: SCAP forms the SREBP-SCAP complex. Reason: Core complex membership, conserved (IBA) and asserted for the fly proteins by the curators. |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IBA GO_REF:0000033 | REMOVE | Summary: IBA for positive regulation of cholesterol biosynthetic process, propagated from vertebrate SCAP. Reason: Insects are cholesterol auxotrophs and lack de novo sterol biosynthesis, so SCAP cannot regulate a cholesterol biosynthetic process in Drosophila; the fly SREBP-SCAP system instead controls fatty acid and phospholipid synthesis. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000847352 SUPPORTS SOURCE BUT NOT TARGET Human SCAP (Q12770) promotes cholesterol biosynthesis via SREBP2, but the pathway does not exist in sterol-auxotrophic insects. Supporting Evidence: PMID:9632664 This is notable, since insects are reportedly incapable of de novo sterol biosynthesis. PMID:11988566 The finding that SREBP processing is controlled by different lipids in mammals and flies (sterols and phosphatidylethanolamine, respectively) |
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