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Protein

Sterol regulatory element-binding protein cleavage-activating protein

Gene

SCAP

Organism
Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Escort protein required for cholesterol as well as lipid homeostasis. Regulates export of the SCAP/SREBF complex from the ER upon low cholesterol. Formation of a ternary complex with INSIG at high sterol concentrations leads to masking of an ER-export signal in SCAP and retention of the complex in the ER. Low sterol concentrations trigger release of INSIG, a conformational change in the SSC domain of SCAP, unmasking of the ER export signal, recruitment into COPII-coated vesicles, transport to the Golgi complex, proteolytic cleavage of SREBF in the Golgi, release of the transcription factor fragment of SREBF from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway.5 Publications

GO - Molecular functioni

  • cholesterol binding Source: InterPro
  • protein C-terminus binding Source: UniProtKB

GO - Biological processi

  • cargo loading into COPII-coated vesicle Source: UniProtKB
  • cholesterol metabolic process Source: UniProtKB-KW
  • establishment of protein localization to Golgi Source: UniProtKB
  • SREBP signaling pathway Source: UniProtKB
  • sterol regulatory element binding protein import into nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Protein family/group databases

TCDBi2.A.6.6.4. the resistance-nodulation-cell division (rnd) superfamily.

Names & Taxonomyi

Protein namesi
Recommended name:
Sterol regulatory element-binding protein cleavage-activating protein
Short name:
SCAP
Short name:
SREBP cleavage-activating protein
Gene namesi
Name:SCAP
OrganismiCricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
Taxonomic identifieri10029 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaCricetidaeCricetinaeCricetulus

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 1818Cytoplasmic1 PublicationAdd
BLAST
Transmembranei19 – 3921Helical; Name=1Sequence analysisAdd
BLAST
Topological domaini40 – 279240Lumenal1 PublicationAdd
BLAST
Transmembranei280 – 30021Helical; Name=2Sequence analysisAdd
BLAST
Topological domaini301 – 31212Cytoplasmic1 PublicationAdd
BLAST
Transmembranei313 – 33321Helical; Name=3Sequence analysisAdd
BLAST
Topological domaini334 – 34411Lumenal1 PublicationAdd
BLAST
Transmembranei345 – 36521Helical; Name=4Sequence analysisAdd
BLAST
Topological domaini366 – 40136Cytoplasmic1 PublicationAdd
BLAST
Transmembranei402 – 42221Helical; Name=5Sequence analysisAdd
BLAST
Topological domaini423 – 4231Lumenal1 Publication
Transmembranei424 – 44421Helical; Name=6Sequence analysisAdd
BLAST
Topological domaini445 – 51874Cytoplasmic1 PublicationAdd
BLAST
Transmembranei519 – 53921Helical; Name=7Sequence analysisAdd
BLAST
Topological domaini540 – 708169Lumenal1 PublicationAdd
BLAST
Transmembranei709 – 72921Helical; Name=8Sequence analysisAdd
BLAST
Topological domaini730 – 1276547Cytoplasmic1 PublicationAdd
BLAST

GO - Cellular componenti

  • endoplasmic reticulum Source: UniProtKB
  • endoplasmic reticulum membrane Source: Reactome
  • ER to Golgi transport vesicle membrane Source: UniProtKB-SubCell
  • Golgi membrane Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasmic vesicle, Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Disruption phenotypei

CHO cells show loss of site-1 cleavage of SREBF1/2, reduced synthesis of cholesterol, a reduced level of LDLR and cholesterol auxotrophy.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi298 – 2981Y → C: Loss of sterol-dependent ER retention due to loss of interaction with INSIG. Constitutive interaction with COPII coat and maturation of SREBF. 4 Publications
Mutagenesisi315 – 3151L → F: Loss of sterol-dependent ER retention due to loss of interaction with INSIG. Constitutive maturation of SREBF. 1 Publication
Mutagenesisi428 – 4281D → A, N or K: Loss of release from ER retention and maturation of SREBF. Constitutive interaction with INSIG. 1 Publication
Mutagenesisi428 – 4281D → E: Very mild reduction of SREBF maturation. Slightly higher affinity for INSIG in the absence of sterols. 1 Publication
Mutagenesisi437 – 4382TT → AA: No effect. 1 Publication
Mutagenesisi437 – 4382Missing : Loss of SREBF maturation and interaction with COPII coat. 1 Publication
Mutagenesisi439 – 4402Missing : Loss of SREBF maturation. 1 Publication
Mutagenesisi439 – 4391V → VLL: Loss of SREBF maturation. 1 Publication
Mutagenesisi443 – 4431D → N: Loss of sterol-dependent ER retention due to loss of interaction with INSIG. 2 Publications
Mutagenesisi444 – 4452Missing : Loss of SREBF maturation. 1 Publication
Mutagenesisi445 – 4462RR → AA: No effect. 1 Publication
Mutagenesisi446 – 4461R → RA, RAAAAA, RG, RGG or RGS: Loss of SREBF maturation. 1 Publication
Mutagenesisi446 – 4461R → RAA: Loss of SREBF maturation and interaction with COPII coat. 1 Publication
Mutagenesisi447 – 4482ME → AA: Loss of SREBF maturation and interaction with COPII coat. 1 Publication
Mutagenesisi449 – 4491L → A: Loss of SREBF maturation and interaction with COPII coat. 1 Publication
Mutagenesisi451 – 4522DL → AA: Loss of SREBF maturation, interaction with COPII coat and recruitment into COPII-coated vesicles. 1 Publication
Mutagenesisi453 – 4531N → NAAAAA: No effect. 1 Publication
Mutagenesisi463 – 49230Missing : No effect. Add
BLAST

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 12761276Sterol regulatory element-binding protein cleavage-activating proteinPRO_0000051207Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi263 – 2631N-linked (GlcNAc...)1 Publication
Glycosylationi590 – 5901N-linked (GlcNAc...)1 Publication
Glycosylationi641 – 6411N-linked (GlcNAc...)1 Publication
Modified residuei821 – 8211PhosphoserineBy similarity
Modified residuei837 – 8371PhosphoserineBy similarity
Modified residuei843 – 8431PhosphoserineBy similarity
Modified residuei850 – 8501PhosphoserineBy similarity
Modified residuei905 – 9051PhosphoserineBy similarity
Modified residuei934 – 9341PhosphoserineBy similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein

Interactioni

Subunit structurei

Membrane region forms a homotetramer. Forms a stable complex with SREBF1/SREBP1 or SREBF2/SREBP2 through its C-terminal cytoplasmic domain. Forms a ternary complex with INSIG1 or INSIG2 through its transmembrane domains at high sterol concentrations. Interacts with the SEC23/SEC24 complex in a SAR1-GTP-dependent manner through an ER export signal in its third cytoplasmic loop. Binds cholesterol through its SSC domain. Component of SCAP/SREBP complex composed of SREBF2, SCAP and RNF139; the complex hampers the interaction between SCAP and SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts with RNF139; the interaction inhibits the interaction of SCAP with SEC24B and hampering the ER to Golgi transport of the SCAP/SREBP complex (By similarity).By similarity

GO - Molecular functioni

  • protein C-terminus binding Source: UniProtKB

Protein-protein interaction databases

BioGridi1613731. 1 interaction.
DIPiDIP-60914N.
IntActiP97260. 1 interaction.

Structurei

3D structure databases

ProteinModelPortaliP97260.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini284 – 442159SSDPROSITE-ProRule annotationAdd
BLAST
Repeati771 – 81141WD 1Add
BLAST
Repeati949 – 99951WD 2Add
BLAST
Repeati1002 – 103938WD 3Add
BLAST
Repeati1074 – 111138WD 4Add
BLAST
Repeati1114 – 115239WD 5Add
BLAST
Repeati1155 – 119238WD 6Add
BLAST
Repeati1194 – 123239WD 7Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni447 – 4526ER export signal
Regioni731 – 1276546Interaction with SREBF2Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi722 – 7298Poly-Leu
Compositional biasi747 – 7504Poly-Arg

Domaini

Cholesterol bound to SSC domain of SCAP or oxysterol bound to INSIG1/2 leads to masking of an ER export signal on SCAP possibly by moving the signal further away from the ER membrane.

Sequence similaritiesi

Belongs to the WD repeat SCAP family.Curated
Contains 1 SSD (sterol-sensing) domain.PROSITE-ProRule annotation
Contains 7 WD repeats.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix, WD repeat

Phylogenomic databases

HOVERGENiHBG019538.

Family and domain databases

Gene3Di2.130.10.10. 3 hits.
InterProiIPR030225. SCAP.
IPR000731. SSD.
IPR015943. WD40/YVTN_repeat-like_dom.
IPR001680. WD40_repeat.
IPR019775. WD40_repeat_CS.
IPR017986. WD40_repeat_dom.
[Graphical view]
PANTHERiPTHR10796:SF127. PTHR10796:SF127. 2 hits.
PfamiPF12349. Sterol-sensing. 1 hit.
PF00400. WD40. 1 hit.
[Graphical view]
SMARTiSM00320. WD40. 6 hits.
[Graphical view]
SUPFAMiSSF50978. SSF50978. 3 hits.
PROSITEiPS50156. SSD. 1 hit.
PS00678. WD_REPEATS_1. 1 hit.
PS50082. WD_REPEATS_2. 1 hit.
PS50294. WD_REPEATS_REGION. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P97260-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MTLTERLREK ISQAFYNHGL LCASYPIPII LFTGLCILAC CYPLLKLPLP
60 70 80 90 100
GTGPVEFSTP VKDYSPPPVD SDHKQGEPSE QPEWYVGAPV AYIQQIFVKS
110 120 130 140 150
SVSPWHKNLL AVDVFRLPLS RAFQLVEEIR NHVLRDSSGT KSLEEVCLQV
160 170 180 190 200
TDLLPGLRKL RNLLPEHGCL LLSPGNFWQN DWERFHADPD IIGTIHQHEP
210 220 230 240 250
KTLQTSATLK DLLFGVPGKY SGVSLYTRKR TVSYTITLVF QRYHAKFLSS
260 270 280 290 300
LRARLMLLHP SPNCSLRAEN LVHVHFKEEI GIAELIPLVT TYIILFAYIY
310 320 330 340 350
FSTRKIDMVK SKWGLALAAV VTVLSSLLMS VGLCTLFGLT PTLNGGEIFP
360 370 380 390 400
YLVVVIGLEN VLVLTKSVVS TPVDLEVKLR IAQGLSSESW SIMKNVATEL
410 420 430 440 450
GIILIGYFTL VPAIQEFCLF AVVGLVSDFF LQMFFFTTVL SIDIRRMELA
460 470 480 490 500
DLNKRLPPES CLPSAKPVGR PARYERQLAV RPAMPHTITL QPSSFRNLRL
510 520 530 540 550
PKRLRVIYFL ARTRLAQRLI MAGTVVWIGI LVYTDPAGLR TYLAAQVTEQ
560 570 580 590 600
SPLGEGSLGP MPVPSGVLPA SRPDPAFSIF PPDAPKLPEN QTVPGELPEH
610 620 630 640 650
AAPAEGVHDS RAPEVTWGPE DEELWRRLSF RHWPTLFNYY NITLAKRYIS
660 670 680 690 700
LLPVIPVTLR LNPQEALEGR QPQDGRSAWA PPESLPAGLW EAGPKGPGGT
710 720 730 740 750
QAHGDITLYK VAALGLAAGI VLVLLLLCLY RVLCPRNYGQ PGGGAGRRRR
760 770 780 790 800
GELPCDDYGY APPETEIVPL VLRGHLMDIE CLASDGMLLV SCCLAGQVCV
810 820 830 840 850
WDAQTGDCLT RIPRPGSRRD SCGGGAFETQ ENWERLSDGG KTSPEEPGES
860 870 880 890 900
PPLRHRPRGP PQPALFGDQP DLTCLIDTNF SVQLPPEPTQ PEPRHRAGCG
910 920 930 940 950
RARDSGYDFS RLVQRVYQEE GLAAVRMPAL RPPSPGSPLP QASQEDGAAP
960 970 980 990 1000
EKGSPPLAWA PSTAGSIWSL ELQGNLIVVG RSSGRLEVWD AIEGVLCCSN
1010 1020 1030 1040 1050
DEVSSGITAL VFLDRRIVAA RLNGSLDFFS LETHTSLSPL QFRGTPGRGS
1060 1070 1080 1090 1100
SPSSSVYSSS NTVACHLTHT VPCAHQKPIT ALRAAAGRLV TGSQDHTLRV
1110 1120 1130 1140 1150
FRLEDSCCLF TLQGHSGAIT TVYIDQTMVL ASGGQDGAIC LWDVLTGSRV
1160 1170 1180 1190 1200
SHTFAHRGDV TSLTCTTSCV ISSGLDDLIN IWDRSTGIKL YSIQQDLGCG
1210 1220 1230 1240 1250
ASLGVISDNL LVTGGQGCVS FWDLNYGDLL QTVYLGKNSE AQPARQILVL
1260 1270
DNAAIVCNFG SELSLVYVPS VLEKLD
Length:1,276
Mass (Da):139,514
Last modified:May 1, 1997 - v1
Checksum:iA8693F7157FF5FFC
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U67060 mRNA. Translation: AAB19103.1.
AF541996 mRNA. Translation: AAQ11376.1.
PIRiT18526.
RefSeqiNP_001230965.1. NM_001244036.1.

Genome annotation databases

GeneIDi100689048.
KEGGicge:100689048.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U67060 mRNA. Translation: AAB19103.1.
AF541996 mRNA. Translation: AAQ11376.1.
PIRiT18526.
RefSeqiNP_001230965.1. NM_001244036.1.

3D structure databases

ProteinModelPortaliP97260.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi1613731. 1 interaction.
DIPiDIP-60914N.
IntActiP97260. 1 interaction.

Protein family/group databases

TCDBi2.A.6.6.4. the resistance-nodulation-cell division (rnd) superfamily.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100689048.
KEGGicge:100689048.

Organism-specific databases

CTDi22937.

Phylogenomic databases

HOVERGENiHBG019538.

Family and domain databases

Gene3Di2.130.10.10. 3 hits.
InterProiIPR030225. SCAP.
IPR000731. SSD.
IPR015943. WD40/YVTN_repeat-like_dom.
IPR001680. WD40_repeat.
IPR019775. WD40_repeat_CS.
IPR017986. WD40_repeat_dom.
[Graphical view]
PANTHERiPTHR10796:SF127. PTHR10796:SF127. 2 hits.
PfamiPF12349. Sterol-sensing. 1 hit.
PF00400. WD40. 1 hit.
[Graphical view]
SMARTiSM00320. WD40. 6 hits.
[Graphical view]
SUPFAMiSSF50978. SSF50978. 3 hits.
PROSITEiPS50156. SSD. 1 hit.
PS00678. WD_REPEATS_1. 1 hit.
PS50082. WD_REPEATS_2. 1 hit.
PS50294. WD_REPEATS_REGION. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein."
    Hua X., Nohturfft A., Goldstein J.L., Brown M.S.
    Cell 87:415-426(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF ASP-443.
    Tissue: Ovary.
  2. "Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols."
    Yabe D., Xia Z.-P., Adams C.M., Rawson R.B.
    Proc. Natl. Acad. Sci. U.S.A. 99:16672-16677(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 56-522, FUNCTION, INTERACTION WITH INSIG1 AND INSIG2, MUTAGENESIS OF TYR-298; LEU-315 AND ASP-443.
    Tissue: Ovary.
  3. "Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies."
    Sakai J., Nohturfft A., Goldstein J.L., Brown M.S.
    J. Biol. Chem. 273:5785-5793(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH SREBF2.
  4. "Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain."
    Nohturfft A., Brown M.S., Goldstein J.L.
    J. Biol. Chem. 273:17243-17250(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: TOPOLOGY, GLYCOSYLATION AT ASN-263; ASN-590 AND ASN-641.
  5. "Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein."
    Rawson R.B., DeBose-Boyd R., Goldstein J.L., Brown M.S.
    J. Biol. Chem. 274:28549-28556(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  6. "Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi."
    Nohturfft A., DeBose-Boyd R.A., Scheek S., Goldstein J.L., Brown M.S.
    Proc. Natl. Acad. Sci. U.S.A. 96:11235-11240(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, CLEAVAGE BY MBTPS1, MUTAGENESIS OF TYR-298.
    Tissue: Ovary.
  7. "Overexpression of membrane domain of SCAP prevents sterols from inhibiting SCAP.SREBP exit from endoplasmic reticulum."
    Yang T., Goldstein J.L., Brown M.S.
    J. Biol. Chem. 275:29881-29886(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  8. "Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER."
    Espenshade P.J., Li W.-P., Yabe D.
    Proc. Natl. Acad. Sci. U.S.A. 99:11694-11699(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH THE SEC23/SEC24 COMPLEX.
  9. "Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain."
    Radhakrishnan A., Sun L.-P., Kwon H.J., Brown M.S., Goldstein J.L.
    Mol. Cell 15:259-268(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT, INTERACTION WITH CHOLESTEROL, MUTAGENESIS OF TYR-298.
  10. "Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro."
    Sun L.-P., Li L., Goldstein J.L., Brown M.S.
    J. Biol. Chem. 280:26483-26490(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ER EXPORT SIGNAL, MUTAGENESIS OF TYR-298; LEU-449; 445-ARG-ARG-446; 447-MET-GLU-448 AND 451-ASP-LEU-452.
  11. "Intramembrane aspartic acid in SCAP protein governs cholesterol-induced conformational change."
    Feramisco J.D., Radhakrishnan A., Ikeda Y., Reitz J., Brown M.S., Goldstein J.L.
    Proc. Natl. Acad. Sci. U.S.A. 102:3242-3247(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH INSIG1 AND INSIG2, MUTAGENESIS OF ASP-428.
  12. "Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins."
    Sun L.-P., Seemann J., Goldstein J.L., Brown M.S.
    Proc. Natl. Acad. Sci. U.S.A. 104:6519-6526(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF VAL-439; ARG-446; ASN-453; 437-THR-THR-438; 439-VAL-LEU-440; 444-ILE-ARG-445 AND 363-PRO--PRO-492.

Entry informationi

Entry nameiSCAP_CRIGR
AccessioniPrimary (citable) accession number: P97260
Secondary accession number(s): Q2WEK9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 16, 2001
Last sequence update: May 1, 1997
Last modified: July 6, 2016
This is version 115 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.