O15503 (INSI1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Insulin-induced gene 1 protein
Short name=INSIG-1

Gene names

Name:

INSIG1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	277 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	Cholesterol metabolism Lipid metabolism Steroid metabolism Sterol metabolism
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transmembrane Transmembrane helix
PTM	Isopeptide bond Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	SREBP 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: Compara cranial suture morphogenesis Inferred from electronic annotation. Source: Compara inner ear morphogenesis Inferred from electronic annotation. Source: Compara metabolic process Traceable author statement Ref.1. Source: ProtInc middle ear morphogenesis Inferred from electronic annotation. Source: Compara 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: Compara negative regulation of fatty acid biosynthetic process Inferred from electronic annotation. Source: Compara negative regulation of steroid biosynthetic process Inferred from electronic annotation. Source: Compara palate development Inferred from electronic annotation. Source: Compara triglyceride metabolic process Inferred from electronic annotation. Source: Compara
Cellular_component	SREBP-SCAP-Insig complex Inferred from direct assay PubMed 15899885. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CYP2C1	P00180	2	EBI-6252425,EBI-6251821	From a different organism.
CYP2C2	P00181	3	EBI-6252425,EBI-4320576	From 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 277	277	Insulin-induced gene 1 protein		PRO_0000191675
Regions
	Topological domain	1 – 87	87	Cytoplasmic Ref.10
	Transmembrane	88 – 108	21	Helical; Potential
	Topological domain	109 – 126	18	Lumenal Potential
	Transmembrane	127 – 147	21	Helical; Potential
	Topological domain	148 – 160	13	Cytoplasmic Ref.10
	Transmembrane	161 – 177	17	Helical; Potential
	Topological domain	178 – 182	5	Lumenal Potential
	Transmembrane	183 – 203	21	Helical; Potential
	Topological domain	204 – 209	6	Cytoplasmic Ref.10
	Transmembrane	210 – 230	21	Helical; Potential
	Topological domain	231 – 241	11	Lumenal Potential
	Transmembrane	242 – 262	21	Helical; Potential
	Topological domain	263 – 277	15	Cytoplasmic Ref.10
Amino acid modifications
	Cross-link	156		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12
	Cross-link	158		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12
Natural variations
	Alternative sequence	138 – 164	27	AVVGL…EWASV → GIHPQISSIFVLGSLVYFSQ EASRWGT in isoform 2.		VSP_045084
	Alternative sequence	165 – 277	113	Missing in isoform 2.		VSP_045085
	Natural variant	27	1	A → T. Ref.1 Corresponds to variant rs1129825 [ dbSNP | Ensembl ].		VAR_027683
Experimental info
	Mutagenesis	156	1	K → R: Loss of ubiquitination and degradation. Ref.12
	Mutagenesis	158	1	K → R: Loss of ubiquitination and degradation. Ref.12
	Mutagenesis	205	1	D → A: Loss of ability to suppress the cleavage of SREBP2 and to accelerate the degradation of HMGCR. Ref.13
	Sequence conflict	31 – 32	2	AA → PP in AAB69121. Ref.1
	Sequence conflict	99	1	A → T in AAB69121. Ref.1
	Sequence conflict	170 – 172	3	VFV → GFG in AAB69121. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 3, 2006. Version 3. Checksum: 198068D53C658A58	FASTA	277	29,987
	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
	Isoform 2 [UniParc]. Checksum: 06076ED6ACE57C04	FASTA	164	17,530
	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 TIFSSAWWVP PCCGTAAGIH PQISSIFVLG SLVYFSQEAS RWGT

References

	« Hide 'large scale' referencesShow '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, 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. , 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. , 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. , 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.
IPI	IPI00290111. IPI01015945.
RefSeq	NP_005533.2. NM_005542.4. NP_938150.2. NM_198336.2. NP_938151.1. NM_198337.2.
UniGene	Hs.520819.
3D structure databases
ProteinModelPortal	O15503.
ModBase	Search...
Protein-protein interaction databases
IntAct	O15503. 2 interactions.
STRING	9606.ENSP00000344741.
PTM databases
PhosphoSite	O15503.
Proteomic databases
PaxDb	O15503.
PRIDE	O15503.
Protocols and materials databases
DNASU	3638.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000340368; ENSP00000344741; ENSG00000186480. ENST00000342407; ENSP00000344035; ENSG00000186480.
GeneID	3638.
KEGG	hsa:3638.
UCSC	uc003wly.3. human.
Organism-specific databases
CTD	3638.
GeneCards	GC07P155089.
HGNC	HGNC:6083. INSIG1.
MIM	602055. gene.
neXtProt	NX_O15503.
PharmGKB	PA29890.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG263628.
HOGENOM	HOG000253021.
HOVERGEN	HBG058958.
OrthoDB	EOG4JDH7K.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism. REACT_147840. SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.
Gene expression databases
ArrayExpress	O15503.
Bgee	O15503.
CleanEx	HS_INSIG1.
Genevestigator	O15503.
GermOnline	ENSG00000186480. Homo sapiens.
Family and domain databases
InterPro	IPR009904. INSIG. IPR025929. INSIG_fam. [Graphical view]
PANTHER	PTHR15301. PTHR15301. 1 hit.
Pfam	PF07281. INSIG. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	INSIG1. human.
GenomeRNAi	3638.
NextBio	14239.
SOURCE	Search...

Entry information

Entry name

INSI1_HUMAN

Accession

Primary (citable) accession number: O15503
Secondary accession number(s): A4D2N1 , A8K6L0, Q53XW8, Q9BUV5

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	October 3, 2006
Last modified:	April 3, 2013
This is version 109 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.