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O15503 (INSI1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Insulin-induced gene 1 protein

Short name=INSIG-1
Gene names
Name:INSIG1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length277 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Mediates feedback control of cholesterol synthesis by controlling SCAP and HMGCR. Functions by blocking the processing of sterol regulatory element-binding proteins (SREBPs). Capable of retaining the SCAP-SREBF2 complex in the ER thus preventing it from escorting SREBPs to the Golgi. Initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase, AMFR/gp78. May play a role in growth and differentiation of tissues involved in metabolic control. May play a regulatory role during G0/G1 transition of cell growth. Ref.2 Ref.9 Ref.11 Ref.12 Ref.13

Subunit structure

Binds to the SCAP-SREBF2 complex only in the presence of sterols. Interacts with RNF139. Interacts with HMGCR (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at the ER membrane for its ubiquitination and degradation by the sterol-mediated ERAD pathway. Ref.2 Ref.9 Ref.11 Ref.12 Ref.14

Subcellular location

Endoplasmic reticulum membrane; Multi-pass membrane protein Ref.2.

Tissue specificity

Expressed in all tissues tested with highest expression in the liver. Ref.2

Induction

By insulin.

Post-translational modification

Ubiquitinated. Subsequent to sterol deprivation, the SCAP-SREBF2 complex becomes dissociated from INSIG1, is then ubiquitinated and degraded in proteasomes. Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex. Ubiquitinated by RNF139. Ref.12 Ref.14

Miscellaneous

Expressed at high levels when nuclear SREBP levels are high as a result of sterol deprivation.

Sequence similarities

Belongs to the INSIG family.

Ontologies

Keywords
   Biological processCholesterol metabolism
Lipid metabolism
Steroid metabolism
Sterol metabolism
   Cellular componentEndoplasmic reticulum
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainTransmembrane
Transmembrane helix
   PTMIsopeptide bond
Ubl conjugation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processSREBP signaling pathway

Inferred from direct assay PubMed 12242332. Source: UniProtKB

cell proliferation

Traceable author statement Ref.1. Source: ProtInc

cholesterol biosynthetic process

Inferred from electronic annotation. Source: Ensembl

cranial suture morphogenesis

Inferred from electronic annotation. Source: Ensembl

inner ear morphogenesis

Inferred from electronic annotation. Source: Ensembl

metabolic process

Traceable author statement Ref.1. Source: ProtInc

middle ear morphogenesis

Inferred from electronic annotation. Source: Ensembl

negative regulation of cargo loading into COPII-coated vesicle

Inferred from mutant phenotype PubMed 15899885. Source: UniProtKB

negative regulation of fat cell differentiation

Inferred from electronic annotation. Source: Ensembl

negative regulation of fatty acid biosynthetic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of steroid biosynthetic process

Inferred from electronic annotation. Source: Ensembl

palate development

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

triglyceride metabolic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentSREBP-SCAP-Insig complex

Inferred from direct assay PubMed 15899885. Source: UniProtKB

endoplasmic reticulum

Inferred from direct assay Ref.2. Source: UniProtKB

endoplasmic reticulum membrane

Traceable author statement. Source: Reactome

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

CYP2C1P001802EBI-6252425,EBI-6251821From a different organism.
CYP2C2P001813EBI-6252425,EBI-4320576From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O15503-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O15503-2)

The sequence of this isoform differs from the canonical sequence as follows:
     138-164: AVVGLLYPCIDSHLGEPHKFKREWASV → GIHPQISSIFVLGSLVYFSQEASRWGT
     165-277: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 277277Insulin-induced gene 1 protein
PRO_0000191675

Regions

Topological domain1 – 8787Cytoplasmic Ref.10
Transmembrane88 – 10821Helical; Potential
Topological domain109 – 12618Lumenal Potential
Transmembrane127 – 14721Helical; Potential
Topological domain148 – 16013Cytoplasmic Ref.10
Transmembrane161 – 17717Helical; Potential
Topological domain178 – 1825Lumenal Potential
Transmembrane183 – 20321Helical; Potential
Topological domain204 – 2096Cytoplasmic Ref.10
Transmembrane210 – 23021Helical; Potential
Topological domain231 – 24111Lumenal Potential
Transmembrane242 – 26221Helical; Potential
Topological domain263 – 27715Cytoplasmic Ref.10

Amino acid modifications

Cross-link156Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12
Cross-link158Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Natural variations

Alternative sequence138 – 16427AVVGL…EWASV → GIHPQISSIFVLGSLVYFSQ EASRWGT in isoform 2.
VSP_045084
Alternative sequence165 – 277113Missing in isoform 2.
VSP_045085
Natural variant271A → T. Ref.1
Corresponds to variant rs1129825 [ dbSNP | Ensembl ].
VAR_027683

Experimental info

Mutagenesis1561K → R: Loss of ubiquitination and degradation. Ref.12
Mutagenesis1581K → R: Loss of ubiquitination and degradation. Ref.12
Mutagenesis2051D → A: Loss of ability to suppress the cleavage of SREBP2 and to accelerate the degradation of HMGCR. Ref.13
Sequence conflict31 – 322AA → PP in AAB69121. Ref.1
Sequence conflict991A → T in AAB69121. Ref.1
Sequence conflict170 – 1723VFV → GFG in AAB69121. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 3, 2006. Version 3.
Checksum: 198068D53C658A58

FASTA27729,987
        10         20         30         40         50         60 
MPRLHDHFWS CSCAHSARRR GPPRASAAGL AAKVGEMINV SVSGPSLLAA HGAPDADPAP 

        70         80         90        100        110        120 
RGRSAAMSGP EPGSPYPNTW HHRLLQRSLV LFSVGVVLAL VLNLLQIQRN VTLFPEEVIA 

       130        140        150        160        170        180 
TIFSSAWWVP PCCGTAAAVV GLLYPCIDSH LGEPHKFKRE WASVMRCIAV FVGINHASAK 

       190        200        210        220        230        240 
LDFANNVQLS LTLAALSLGL WWTFDRSRSG LGLGITIAFL ATLITQFLVY NGVYQYTSPD 

       250        260        270 
FLYIRSWLPC IFFSGGVTVG NIGRQLAMGV PEKPHSD 

« Hide

Isoform 2 [UniParc].

Checksum: 06076ED6ACE57C04
Show »

FASTA16417,530

References

« Hide 'large scale' references
[1]"Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene."
Peng Y., Schwarz E.J., Lazar M.A., Genin A., Spinner N.B., Taub R.
Genomics 43:278-284(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-27.
[2]"Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER."
Yang T., Espenshade P.J., Wright M.E., Yabe D., Gong Y., Aebersold R., Goldstein J.L., Brown M.S.
Cell 110:489-500(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 40-61 AND 64-83, IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH SCAP AND SREBP2 COMPLEX.
[3]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Placenta.
[5]"High-throughput cloning of full-length human cDNAs directly from cDNA libraries optimized for large and rare transcripts."
Birkett C., Cho J., Gau Y., Hamer R., Kelly S., Kovacs K., Liu L., Liu X., Porter J., Sachs A., Shu Y., Sun Z., Wong J., Wu M., Zhang X., Jay G., He W.
Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Mammary tumor.
[6]"Human chromosome 7: DNA sequence and biology."
Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. expand/collapse author list , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C.
Science 300:767-772(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Skin.
[9]"Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain."
Sever N., Yang T., Brown M.S., Goldstein J.L., DeBose-Boyd R.A.
Mol. Cell 11:25-33(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HMGCR, FUNCTION.
[10]"Membrane topology of human insig-1, a protein regulator of lipid synthesis."
Feramisco J.D., Goldstein J.L., Brown M.S.
J. Biol. Chem. 279:8487-8496(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TOPOLOGY.
[11]"Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase."
Song B.L., Sever N., DeBose-Boyd R.A.
Mol. Cell 19:829-840(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AMFR, FUNCTION.
[12]"Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake."
Gong Y., Lee J.N., Lee P.C., Goldstein J.L., Brown M.S., Ye J.
Cell Metab. 3:15-24(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SCAP AND SREBP2 COMPLEX, UBIQUITINATION AT LYS-156 AND LYS-158, MUTAGENESIS OF LYS-156 AND LYS-158.
[13]"Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis."
Gong Y., Lee J.N., Brown M.S., Goldstein J.L., Ye J.
Proc. Natl. Acad. Sci. U.S.A. 103:6154-6159(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF ASP-205.
[14]"The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways."
Lee J.P., Brauweiler A., Rudolph M., Hooper J.E., Drabkin H.A., Gemmill R.M.
Mol. Cancer Res. 8:93-106(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RNF139, UBIQUITINATION BY RNF139.
+Additional computationally mapped references.

Web resources

Wikipedia

Insig1 entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U96876 Genomic DNA. Translation: AAB69121.1.
AY112745 mRNA. Translation: AAM44086.1.
BT007227 mRNA. Translation: AAP35891.1.
AK291675 mRNA. Translation: BAF84364.1.
DN996424 mRNA. No translation available.
AC144652 Genomic DNA. No translation available.
AC231970 Genomic DNA. No translation available.
CH236962 Genomic DNA. Translation: EAL23729.1.
CH236962 Genomic DNA. Translation: EAL23730.1.
CH471149 Genomic DNA. Translation: EAX04529.1.
CH471149 Genomic DNA. Translation: EAX04530.1.
BC001880 mRNA. Translation: AAH01880.1.
RefSeqNP_005533.2. NM_005542.4.
NP_938150.2. NM_198336.2.
NP_938151.1. NM_198337.2.
UniGeneHs.520819.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4J81X-ray1.74C/D273-277[»]
ProteinModelPortalO15503.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109850. 20 interactions.
IntActO15503. 5 interactions.
MINTMINT-4723340.
STRING9606.ENSP00000344741.

PTM databases

PhosphoSiteO15503.

Proteomic databases

PaxDbO15503.
PRIDEO15503.

Protocols and materials databases

DNASU3638.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000340368; ENSP00000344741; ENSG00000186480. [O15503-1]
ENST00000342407; ENSP00000344035; ENSG00000186480. [O15503-2]
GeneID3638.
KEGGhsa:3638.
UCSCuc003wly.3. human. [O15503-1]
uc003wlz.3. human.

Organism-specific databases

CTD3638.
GeneCardsGC07P155089.
HGNCHGNC:6083. INSIG1.
MIM602055. gene.
neXtProtNX_O15503.
PharmGKBPA29890.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG263628.
HOGENOMHOG000253021.
HOVERGENHBG058958.
OMAAMSGPEP.
OrthoDBEOG7RNK13.
PhylomeDBO15503.
TreeFamTF331013.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
REACT_147840. SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.

Gene expression databases

ArrayExpressO15503.
BgeeO15503.
CleanExHS_INSIG1.
GenevestigatorO15503.

Family and domain databases

InterProIPR009904. INSIG.
IPR025929. INSIG_fam.
[Graphical view]
PANTHERPTHR15301:SF4. PTHR15301:SF4. 1 hit.
PfamPF07281. INSIG. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSINSIG1. human.
GeneWikiINSIG1.
GenomeRNAi3638.
NextBio14239.
PROO15503.
SOURCESearch...

Entry information

Entry nameINSI1_HUMAN
AccessionPrimary (citable) accession number: O15503
Secondary accession number(s): A4D2N1 expand/collapse secondary AC list , A8K6L0, Q53XW8, Q9BUV5
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: October 3, 2006
Last modified: April 16, 2014
This is version 117 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM