SCAP (SREBP cleavage-activating protein, SREBF chaperone) is a polytopic membrane protein of the endoplasmic reticulum that acts as the cell's cholesterol sensor and as the escort that delivers the membrane-bound transcription factors SREBP-1 and SREBP-2 from the ER to the Golgi. Its N-terminal eight-transmembrane region contains a sterol-sensing domain that binds cholesterol, and its C-terminal cytosolic WD40 domain binds the regulatory domain of SREBPs, forming a stable SREBP-SCAP complex. When ER cholesterol is low, a cytosolic loop of SCAP exposes the MELADL sorting signal, which is bound by the COPII proteins Sar1-Sec23/Sec24, so the SCAP-SREBP complex is packaged into COPII vesicles and travels to the Golgi; there the proteases S1P and S2P release the SREBP transcription-factor domain, which activates genes for cholesterol and fatty-acid synthesis and LDL uptake. SCAP then returns to the ER. When ER cholesterol rises, cholesterol binding to luminal loop 1 changes SCAP's conformation, promoting binding to the ER anchor proteins INSIG1/INSIG2 (which also bind oxysterols), masking MELADL and retaining the complex in the ER. This gives end-product feedback control of cellular cholesterol. The Golgi protein PAQR3, the E3 ligases RNF139 and RNF145, and the Golgi factor SPRING1 modulate SCAP trafficking.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | EXP PMID:26311497 PAQR3 modulates cholesterol homeostasis by anchoring Scap/SR... | ACCEPT | Summary: Subcellular fractionation and immunofluorescence show Scap shifting from ER to Golgi fractions upon sterol depletion, and PAQR3 anchors Scap/SREBP in the Golgi. Reason: SCAP cycles: in sterol-depleted cells the SCAP-SREBP complex moves in COPII vesicles to the Golgi, where SREBP is cleaved by S1P/S2P and SCAP returns to the ER by COPI transport. Golgi membrane residence is an intrinsic part of its escort cycle. Supporting Evidence: PMID:26311497 On LD, the majority of Scap was shifted to the Golgi fractions in SRD-13A cells PMID:26311497 PAQR3 interacts with Scap/SREBP and tethers them to the Golgi complex, resulting in enhanced SREBP processing and cellular cholesterol level |
| GO:0000139 Golgi membrane | IDA PMID:32111832 Haploid genetic screens identify SPRING/C12ORF49 as a determ... | ACCEPT | Summary: SCAP-eGFP relocates from ER to Golgi on sterol depletion; in SPRING-deficient cells it is trapped in the Golgi. Reason: SCAP cycles: in sterol-depleted cells the SCAP-SREBP complex moves in COPII vesicles to the Golgi, where SREBP is cleaved by S1P/S2P and SCAP returns to the ER by COPI transport. Golgi membrane residence is an intrinsic part of its escort cycle. Supporting Evidence: PMID:32111832 In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion PMID:32111832 The final step in the SCAP-SREBP cycle is the less-well understood COPI-mediated retrograde transport of SCAP from the Golgi to the ER |
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro SCAP family / UniProt subcellular location) for Golgi membrane. Reason: SCAP cycles: in sterol-depleted cells the SCAP-SREBP complex moves in COPII vesicles to the Golgi, where SREBP is cleaved by S1P/S2P and SCAP returns to the ER by COPI transport. Golgi membrane residence is an intrinsic part of its escort cycle. Consistent with the experimental rows. Supporting Evidence: PMID:32111832 In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion PMID:26311497 On LD, the majority of Scap was shifted to the Golgi fractions in SRD-13A cells |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655842 | ACCEPT | Summary: Reactome places SCAP (as part of the SCAP-SREBP complex) on the Golgi membrane at the S1P cleavage step. Reason: SCAP cycles: in sterol-depleted cells the SCAP-SREBP complex moves in COPII vesicles to the Golgi, where SREBP is cleaved by S1P/S2P and SCAP returns to the ER by COPI transport. Golgi membrane residence is an intrinsic part of its escort cycle. The Reactome event summary describes the S1P cleavage itself; SCAP's presence in the Golgi is supported experimentally. Supporting Evidence: PMID:26311497 On LD, the majority of Scap was shifted to the Golgi fractions in SRD-13A cells PMID:26311497 PAQR3 interacts with Scap/SREBP and tethers them to the Golgi complex, resulting in enhanced SREBP processing and cellular cholesterol level |
| GO:0005515 protein binding | IPI PMID:17428920 Sterol-regulated transport of SREBPs from endoplasmic reticu... | REMOVE | Summary: Interaction of SCAP with INSIG2 (oxysterol-dependent). Reason: Generic protein binding is uninformative. The SCAP-INSIG interaction is real and central (cholesterol-bound SCAP and oxysterol-bound INSIG associate), but it is better captured by the SREBP-SCAP-Insig complex (GO:0032937) and by SCAP's sterol sensor/cholesterol binding activities. Removal does not mean the interaction is false. Supporting Evidence: PMID:17428920 Cholesterol acts by binding to the SREBP-escort protein Scap, thereby causing Scap to bind to anchor proteins called Insigs. |
| GO:0005515 protein binding | IPI PMID:19706601 The sterol-sensing endoplasmic reticulum (ER) membrane prote... | REMOVE | Summary: Interaction of SCAP with the ER E3 ligase RNF139/TRC8, which hampers SCAP-Sec24 interaction. Reason: Generic protein binding is uninformative; TRC8 is a regulator of SCAP, and no more specific SCAP molecular function follows from this interaction. Removal does not mean the interaction is false. Supporting Evidence: PMID:19706601 TRC8 is capable of binding both SREBP-2 and SREBP cleavage-activated protein (SCAP), thereby forming a TRC8.SREBP-2.SCAP complex. |
| GO:0005515 protein binding | IPI PMID:32111832 Haploid genetic screens identify SPRING/C12ORF49 as a determ... | REMOVE | Summary: Co-immunoprecipitation of overexpressed SCAP with the Golgi protein SPRING1 (C12orf49). Reason: Generic protein binding is uninformative; the interaction was shown with overexpressed proteins and does not define a SCAP activity. Removal does not mean the interaction is false. Supporting Evidence: PMID:32111832 We used a co-immunoprecipitation approach and found that SCAP can interact with SPRING when the two are over-expressed in a model system |
| GO:0005783 endoplasmic reticulum | NAS PMID:11726962 A new feature on the cholesterol-lowering landscape. | MODIFY | Summary: Author statement (Nat Med commentary on liver Scap knockout) that SCAP is in the ER. Reason: Correct but general: SCAP is an integral ER membrane protein; the review accepts endoplasmic reticulum membrane (GO:0005789), which the gene already carries with IDA and IBA support. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex PMID:32111832 In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for ER membrane placed at the SCAP family node (PTN001648672), with human SCAP and mouse Scap among descendant evidence. Reason: SCAP is a polytopic ER membrane protein; in sterol-replete cells it resides in the ER membrane, retained there by INSIG binding. The node placement is sound: SCAP orthologues across animals and fungi (Scp1 in S. pombe) are ER membrane sterol sensors; human SCAP appearing in WITH/FROM reflects its own experimental grounding. Supporting Evidence: PMID:32111832 In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:32111832 Haploid genetic screens identify SPRING/C12ORF49 as a determ... | ACCEPT | Summary: SCAP-eGFP co-localizes with an ER marker in sterol-replete cells. Reason: SCAP is a polytopic ER membrane protein; in sterol-replete cells it resides in the ER membrane, retained there by INSIG binding. Supporting Evidence: PMID:32111832 In control cells grown in sterol-containing media SCAP-eGFP was predominantly located in the ER and localization markedly shifted towards the Golgi upon sterol-depletion |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA for ER membrane. Reason: SCAP is a polytopic ER membrane protein; in sterol-replete cells it resides in the ER membrane, retained there by INSIG binding. Supporting Evidence: PMID:26311497 Consistent with our fractionation results and previous studies11, Scap was mainly co-localized with an ER marker calnexin in normal medium. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: Author statement that SCAP is retained in the ER membrane by INSIG-1. Reason: SCAP is a polytopic ER membrane protein; in sterol-replete cells it resides in the ER membrane, retained there by INSIG binding. Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0005794 Golgi apparatus | NAS PMID:11726962 A new feature on the cholesterol-lowering landscape. | MODIFY | Summary: Author statement that SCAP moves to the Golgi. Reason: Correct but general: SCAP is a multi-pass membrane protein, so its Golgi location is Golgi membrane (GO:0000139), which the gene already carries with EXP/IDA support. Proposed replacements: Golgi membrane Supporting Evidence: PMID:26311497 On LD, the majority of Scap was shifted to the Golgi fractions in SRD-13A cells |
| GO:0005794 Golgi apparatus | NAS PMID:23564452 Point mutation in luminal loop 7 of Scap protein blocks inte... | MODIFY | Summary: Loop 7 Y640S mutation blocks Scap movement to the Golgi; implies Golgi localization of wild-type Scap. Reason: Correct but general: Golgi membrane (GO:0000139) is the precise location for this polytopic protein and is already carried by the gene. Proposed replacements: Golgi membrane Supporting Evidence: PMID:23564452 Here, we create a point mutation (Y640S) in luminal Loop 7 that prevents Scap movement to Golgi. PMID:26311497 On LD, the majority of Scap was shifted to the Golgi fractions in SRD-13A cells |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | MARK AS OVER ANNOTATED | Summary: ComplexPortal annotation of the SREBP-SCAP complex to regulation of Pol II transcription, from a study of a SCAP degrader (lycorine) that lowers SREBP target gene expression. Reason: SCAP itself acts in the ER/Golgi membrane; it controls whether SREBP is delivered for proteolytic activation and so acts upstream of transcription. The transcriptional regulatory activity belongs to the released SREBP N-terminal fragment. The complex-level term propagated to SCAP over-states SCAP's role; the SREBP signaling pathway (GO:0032933) and positive regulation of cholesterol biosynthetic process (GO:0045542) capture what SCAP does. Supporting Evidence: PMID:32432943 Without SCAP, SREBFs in the ER are unstable and cannot translocate to the Golgi apparatus. PMID:32432943 In hepatic Scap -deficient mice, all three SREBFs in the nucleus reduced dramatically, leading to an 80% decrease of cholesterol and fatty acid synthesis rate in the liver. |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MARK AS OVER ANNOTATED | Summary: ComplexPortal NAS for the SREBP-SCAP complex in regulation of Pol II transcription. Reason: As for the IDA row: SCAP regulates SREBP export and processing, not transcription directly; the term is properly carried by SREBF1/SREBF2. Supporting Evidence: PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases |
| GO:0008203 cholesterol metabolic process | IDA PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | MODIFY | Summary: ComplexPortal IDA: SCAP degradation lowers cellular cholesterol and SREBP target gene expression. Reason: SCAP does not catalyse any step of cholesterol metabolism; it regulates cholesterol synthesis (and uptake) by controlling SREBP activation. The regulatory term positive regulation of cholesterol biosynthetic process (GO:0045542), already carried by the gene, is the accurate replacement. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:32432943 In hepatic Scap -deficient mice, all three SREBFs in the nucleus reduced dramatically, leading to an 80% decrease of cholesterol and fatty acid synthesis rate in the liver. PMID:32432943 Without SCAP, SREBFs in the ER are unstable and cannot translocate to the Golgi apparatus. |
| GO:0008203 cholesterol metabolic process | ISS GO_REF:0000024 | MODIFY | Summary: ISS from hamster Scap (P97260) for cholesterol metabolic process. Reason: SCAP is a regulator, not a metabolic enzyme; replace with positive regulation of cholesterol biosynthetic process (GO:0045542). Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:8898195 SREBP cleavage-activating protein (SCAP), which regulates cholesterol metabolism by stimulating cleavage of transcription factors SREBP-1 and -2, thereby releasing them from membranes |
| GO:0008203 cholesterol metabolic process | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MODIFY | Summary: ComplexPortal NAS for cholesterol metabolic process. Reason: SCAP regulates, rather than performs, cholesterol metabolism; replace with GO:0045542. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. |
| GO:0012507 ER to Golgi transport vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (COPII-coated vesicle membrane) to ER to Golgi transport vesicle membrane. Reason: SCAP is packaged with SREBP into COPII vesicles via its MELADL signal; hamster Scap has direct evidence in COPII vesicles. This location is integral to its escort function. Supporting Evidence: PMID:15899885 Sorting of SREBPs into COPII vesicles is mediated by Sar1 and the coat proteins Sec23 and Sec24. PMID:15899885 Sec23/24 binding to Scap requires the hexapeptide sequence MELADL located in a cytoplasmic loop of Scap. This hexapeptide acts as a sterol-regulated ER sorting signal. |
| GO:0016020 membrane | NAS PMID:11726962 A new feature on the cholesterol-lowering landscape. | TOO GENERAL | Summary: Author statement that SCAP is a membrane protein. Reason: True but uninformative: endoplasmic reticulum membrane and Golgi membrane are accepted in this review and entail membrane. Supporting Evidence: PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex |
| GO:0032933 SREBP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA placing SREBP signaling pathway at the SCAP family node, with S. pombe Scp1 and human SCAP as descendant evidence. Reason: Core process. SCAP is the sterol-regulated escort that moves SREBP to the Golgi for activation; the fission yeast Scp1-Sre1 system is the same pathway, so the node placement spanning fungi and animals is sound. Supporting Evidence: PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases PMID:8898195 SREBP cleavage-activating protein (SCAP), which regulates cholesterol metabolism by stimulating cleavage of transcription factors SREBP-1 and -2, thereby releasing them from membranes |
| GO:0032933 SREBP signaling pathway | IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li... | ACCEPT | Summary: PCK1-mediated INSIG phosphorylation releases SCAP-SREBP for Golgi translocation and SREBP activation. Reason: Core process; SCAP's participation in SREBP signaling is established by many studies. The cached abstract shows SREBP activation depends on SCAP-SREBP release and translocation; defer to the curator on details. Supporting Evidence: PMID:32322062 disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IPR030225 SCAP family) mapping to SREBP signaling pathway. Reason: Core process, consistent with experimental and IBA rows. Supporting Evidence: PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases |
| GO:0032933 SREBP signaling pathway | IMP PMID:11726962 A new feature on the cholesterol-lowering landscape. | ACCEPT | Summary: IMP: liver-specific Scap knockout (discussed in this Nat Med commentary) abolishes SREBP processing. Reason: Core process. The cached record has no abstract, but the conclusion (SCAP required for SREBP activation) is independently established, e.g. nuclear SREBFs are greatly reduced in hepatic Scap-deficient mice. Supporting Evidence: PMID:32432943 In hepatic Scap -deficient mice, all three SREBFs in the nucleus reduced dramatically, leading to an 80% decrease of cholesterol and fatty acid synthesis rate in the liver. PMID:32432943 Without SCAP, SREBFs in the ER are unstable and cannot translocate to the Golgi apparatus. |
| GO:0032934 sterol binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IPR030225) mapping to sterol binding. Reason: Correct but general: SCAP's sterol-sensing domain binds cholesterol directly with high affinity and specificity, and cholesterol binding (GO:0015485, is_a sterol binding) is the precise term. SCAP also contacts 25-hydroxycholesterol at the SCAP-INSIG-2 interface, but oxysterol regulation is mediated mainly through INSIG binding. The binding is the input to SCAP's sterol sensor activity (GO:0032935, proposed NEW). Proposed replacements: cholesterol binding Supporting Evidence: PMID:15260976 cholesterol acts by binding with high affinity and specificity to the 767 amino acid octahelical membrane region of SCAP PMID:33446483 A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. |
| GO:0032934 sterol binding | ISS GO_REF:0000024 | MODIFY | Summary: ISS from hamster Scap (P97260), which binds cholesterol in purified form. Reason: Correct but general; replace with cholesterol binding (GO:0015485), directly shown for the purified Scap membrane domain. Proposed replacements: cholesterol binding Supporting Evidence: PMID:15260976 cholesterol acts by binding with high affinity and specificity to the 767 amino acid octahelical membrane region of SCAP PMID:17428920 Cholesterol acts by binding to the SREBP-escort protein Scap, thereby causing Scap to bind to anchor proteins called Insigs. |
| GO:0032936 SREBP-SCAP complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for SREBP-SCAP complex at the SCAP family node. Reason: SCAP forms a stable complex with SREBPs through its WD40 domain immediately after synthesis; conserved in fungi (Scp1-Sre1). Supporting Evidence: PMID:16399501 Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases |
| GO:0032936 SREBP-SCAP complex | IPI PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | ACCEPT | Summary: Co-immunoprecipitation of the SCAP/SREBP complex with insig-2. Reason: SCAP is a defining subunit of the SREBP-SCAP complex. Supporting Evidence: PMID:12242332 We demonstrate that insig-2 can also bind the SCAP/SREBP complex and cause its retention in the ER in a sterol-dependent fashion. |
| GO:0032936 SREBP-SCAP complex | IPI PMID:32432943 Discovery of a potent SCAP degrader that ameliorates HFD-ind... | ACCEPT | Summary: Endogenous SCAP-SREBF1 interaction in hepatocytes (reduced by lycorine). Reason: SCAP is a defining subunit of the SREBP-SCAP complex. Supporting Evidence: PMID:32432943 Consistently, lycorine increased endogenous SCAP-SQSTM1 interaction, reduced SCAP-INSIG1, and SCAP-SREBF1 interaction in hepatocytes |
| GO:0032937 SREBP-SCAP-Insig complex | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: Sterols induce SCAP/SREBP binding to INSIG-1 (blue native PAGE, co-IP). Reason: The sterol-induced SREBP-SCAP-INSIG complex is the ER-retained state of SCAP and the output of its sterol sensing. Supporting Evidence: PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER. PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | TOO GENERAL | Summary: Ensembl Compara transfer from rat of protein-containing complex. Reason: True but uninformative: SREBP-SCAP complex and SREBP-SCAP-Insig complex are accepted and entail it. Supporting Evidence: PMID:16399501 Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. |
| GO:0033552 response to vitamin B3 | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of response to vitamin B3 from rat Scap. Reason: The rat source annotation (RGD, PMID:19878707) is an expression-pattern (IEP) annotation, i.e. a change in Scap expression after niacin treatment. A transcript-level response is not a function of the SCAP protein, and propagating an IEP-derived response term electronically to human is not justified. Supporting Evidence: PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of protein-containing complex binding from rat Scap. Reason: Uninformative binding term transferred from a rat IPI annotation (PMID:19158095). The complexes whose binding defines SCAP's function are the COPII Sec23/Sec24 coat complex, bound via the MELADL signal, and its SREBP cargo bound simultaneously by the WD40 domain; together this is cargo receptor activity (GO:0038024), proposed NEW in this review. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:15899885 Sec23/24 binding to Scap requires the hexapeptide sequence MELADL located in a cytoplasmic loop of Scap. This hexapeptide acts as a sterol-regulated ER sorting signal. PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases |
| GO:0045541 negative regulation of cholesterol biosynthetic process | NAS PMID:11969205 Cholesterol, hydroxycholesterols, and bile acids. | KEEP AS NON CORE | Summary: Review on oxysterols stating that downregulation of cholesterol synthesis by hydroxycholesterols proceeds via the SREBP/SCAP pathway. Reason: SCAP is the sterol-regulated switch: when cholesterol binds SCAP (or oxysterol-bound INSIG binds SCAP), SCAP-SREBP is retained in the ER and cholesterol synthesis is shut down. This feedback inhibition is a genuine consequence of SCAP's sensor activity, but the main informative role, captured by GO:0045542 and GO:0032933, is SREBP activation. Supporting Evidence: PMID:17428920 Cholesterol acts by binding to the SREBP-escort protein Scap, thereby causing Scap to bind to anchor proteins called Insigs. PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER. |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for positive regulation of cholesterol biosynthetic process (PTN000847352). Reason: SCAP is required for SREBP-2 activation and thus for induction of cholesterol synthesis genes; liver Scap deficiency reduces cholesterol synthesis by ~80%. Node placement within vertebrate SCAP is sound. Supporting Evidence: PMID:32432943 In hepatic Scap -deficient mice, all three SREBFs in the nucleus reduced dramatically, leading to an 80% decrease of cholesterol and fatty acid synthesis rate in the liver. PMID:8898195 SREBP cleavage-activating protein (SCAP), which regulates cholesterol metabolism by stimulating cleavage of transcription factors SREBP-1 and -2, thereby releasing them from membranes |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li... | ACCEPT | Summary: SCAP-SREBP release and Golgi translocation drive SREBP activation and lipogenic gene transcription. Reason: Core regulatory process for SCAP. Supporting Evidence: PMID:32322062 disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) |
| GO:0090110 COPII-coated vesicle cargo loading | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from hamster Scap for COPII-coated vesicle cargo loading. Reason: Core process: SCAP's MELADL signal binds Sar1-dependent Sec23/24, loading SCAP-SREBP into COPII vesicles; sterols block this. SCAP performs this step itself as the cargo receptor for SREBP. Supporting Evidence: PMID:15899885 Sec23/24 binding to Scap requires the hexapeptide sequence MELADL located in a cytoplasmic loop of Scap. This hexapeptide acts as a sterol-regulated ER sorting signal. PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig. |
| GO:0032935 sterol sensor activity | IDA PMID:15260976 Direct binding of cholesterol to the purified membrane regio... | NEW | Summary: SCAP binds cholesterol in its sterol-sensing membrane domain and responds with a conformational change that controls COPII binding. Reason: Sterol sensor activity (binding to and responding, e.g. by conformational change, to changes in the cellular level of a sterol) is the defining activity of SCAP and is not represented in GOA, which carries only sterol binding. Purified SCAP membrane domain binds cholesterol with high affinity and specificity; cholesterol changes SCAP conformation (trypsin protection), is proposed to disrupt the luminal Loop1-Loop7 interaction (still unproven, PMID:27068746), and hides the cytosolic MELADL signal from COPII. Comparator check: this term is carried by other cholesterol sensors such as SLC38A9 and OSBPL1A, so its absence from SCAP is a gap rather than a convention. The data are largely from hamster Scap; the human Scap-INSIG-2 structure shows the same sterol-sensing domain arrangement. Supporting Evidence: PMID:15260976 cholesterol acts by binding with high affinity and specificity to the 767 amino acid octahelical membrane region of SCAP PMID:12963821 the conformation of SCAP is altered in vitro by addition of cholesterol to ER membranes PMID:27068746 When ER cholesterol rises, it binds to Loop1. We hypothesized that this causes dissociation from Loop7, abrogating COPII binding. PMID:17428919 Cysteine labeling shows that both binding events produce a conformational change near the MELADL sequence, abrogating COPII binding but not anti-MELADL binding. |
| GO:0038024 cargo receptor activity | IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ... | NEW | Summary: SCAP binds its SREBP cargo through the WD40 domain and the COPII Sec23/Sec24 coat through the MELADL signal, recruiting SREBP into COPII vesicles. Reason: SCAP's escort role matches the definition of cargo receptor activity: a membrane-spanning protein that binds cargo and coat adaptors at the same time to recruit cargo into nascent vesicles. SREBPs bind SCAP from synthesis onward and cannot leave the ER without it; Sar1-dependent Sec23/24 binding to SCAP requires MELADL, and blocking MELADL blocks SCAP-SREBP movement. Comparator check: other ER-exit COPII cargo receptors (CNIH1/CNIH2 by IBA, LMAN1, MIA3) carry this term. GO has no SREBP-specific escort term; see suggested_questions. Supporting Evidence: PMID:15899885 Sec23/24 binding to Scap requires the hexapeptide sequence MELADL located in a cytoplasmic loop of Scap. This hexapeptide acts as a sterol-regulated ER sorting signal. PMID:17428919 anti-MELADL blocks COPII binding in vitro, and microinjection of Fab anti-MELADL blocks Scap.SREBP movement in cells PMID:12242332 In sterol-depleted cells, SCAP escorts SREBPs to the Golgi where the SREBPs are processed by two membrane-bound proteases PMID:32432943 Without SCAP, SREBFs in the ER are unstable and cannot translocate to the Golgi apparatus. |
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Download this section (compressed HTML)Q: Should GO gain a specific child of cargo receptor activity for sterol-regulated ER export of SREBPs (an 'SREBP escort' activity), or is GO:0038024 cargo receptor activity the intended term for SCAP's role? SCAP carries no informative molecular function in GOA beyond sterol binding.
Q: The human GO-CAM gocams/6205c24300000880 (SREBP regulation and retention by the SREBP-SCAP complex) has no SCAP activity node; the SREBP-SCAP complex appears only as an input to INSIG sequestering activity. Should SCAP be added with sterol sensor activity and cargo receptor activity (part of COPII-coated vesicle cargo loading), causally upstream of S1P/S2P cleavage of SREBP?
Q: Is the ComplexPortal-derived 'regulation of transcription by RNA polymerase II' annotation for every SREBP-SCAP complex subunit intended? SCAP acts in the ER/Golgi membrane upstream of SREBP release and has no transcriptional activity of its own.
Q: How does SCAP's direct binding of 25-hydroxycholesterol at the SCAP-INSIG-2 interface relate to the model in which oxysterols act only by binding INSIG? Does SCAP contribute to oxysterol sensing as a composite site?
Experiment: Reconstitute purified human SCAP (wild type, Y298C, D443N and Loop1/Loop7 mutants) in proteoliposomes with defined cholesterol content and measure Sec23/Sec24 (Sar1-GTP) binding and INSIG association, to define the cholesterol threshold and cooperativity of the human sensor.
Hypothesis: Human SCAP switches from COPII-binding to INSIG-binding at a sharp ER cholesterol threshold (~5% of ER lipid), set by the SSD.
Type: in vitro biochemical reconstitution
Experiment: Map the retrograde Golgi-to-ER return of SCAP: live imaging of endogenously tagged SCAP in SPRING1, PAQR3 and COPI-depleted human cells, with S1P inhibition, to identify the retrieval signal and the proteins that release SCAP from the Golgi.
Hypothesis: SCAP return to the ER uses a COPI-dependent signal that becomes available after SREBP cleavage and requires SPRING1.
Type: genome editing / live-cell imaging
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