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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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. Seems to regulate the ubiquitin-mediated proteasomal degradation of HMGCR. 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.8 Ref.10 Ref.11
Subunit structure	Binds to the SCAP-SREBF2 complex only in the presence of sterols. Interacts with RNF139. Ref.2 Ref.10 Ref.12
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.10 Ref.12
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
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane Transmembrane helix
PTM	Isopeptide bond Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	ER-nuclear sterol response pathway Inferred from direct assay PubMed 12242332. Source: UniProtKB cell proliferation Traceable author statement Ref.1. Source: ProtInc
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	protein binding Inferred from physical interaction Ref.2PubMed 16168377. Source: UniProtKB
Complete GO annotation...

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.9
	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.9
	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.9
	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.9
Amino acid modifications
	Cross-link	156		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.10
	Cross-link	158		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.10
Natural variations
	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.10
	Mutagenesis	158	1	K → R: Loss of ubiquitination and degradation. Ref.10
	Mutagenesis	205	1	D → A: Loss of ability to suppress the cleavage of SREBP2 and to accelerate the degradation of HMGCR. Ref.11
	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)
	O15503 [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

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: 9268630] [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: 12202038] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], 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].
[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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[5]	"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: 12690205] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	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].
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skin.
[8]	"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: 12535518] [Abstract] Cited for: FUNCTION.
[9]	"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: 14660594] [Abstract] Cited for: TOPOLOGY.
[10]	"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: 16399501] [Abstract] Cited for: FUNCTION, INTERACTION WITH SCAP AND SREBP2 COMPLEX, UBIQUITINATION AT LYS-156 AND LYS-158, MUTAGENESIS OF LYS-156 AND LYS-158.
[11]	"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: 16606821] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-205.
[12]	"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: 20068067] [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. CH236962 Genomic DNA. Translation: EAL23729.1. CH471149 Genomic DNA. Translation: EAX04529.1. BC001880 mRNA. Translation: AAH01880.1.
IPI	IPI00290111.
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
STRING	O15503.
PTM databases
PhosphoSite	O15503.
Proteomic databases
PRIDE	O15503.
Protocols and materials databases
DNASU	3638.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000340368; ENSP00000344741; ENSG00000186480.
GeneID	3638.
KEGG	hsa:3638.
UCSC	uc003wly.3. human.
Organism-specific databases
CTD	3638.
GeneCards	GC07P155089.
H-InvDB	HIX0020113.
HGNC	HGNC:6083. INSIG1.
MIM	602055. gene.
neXtProt	NX_O15503.
PharmGKB	PA29890.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG263628.
GeneTree	ENSGT00580000081600.
HOGENOM	HOG000253021.
HOVERGEN	HBG058958.
OrthoDB	EOG4JDH7K.
Gene expression databases
ArrayExpress	O15503.
Bgee	O15503.
CleanEx	HS_INSIG1.
Genevestigator	O15503.
GermOnline	ENSG00000186480. Homo sapiens.
Family and domain databases
InterPro	IPR009904. INSIG. [Graphical view]
PANTHER	PTHR15301. INSIG. 1 hit.
ProtoNet	Search...
Other
NextBio	14239.
SOURCE	Search...

Entry information

Entry name

INSI1_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	October 3, 2006
Last modified:	May 16, 2012
This is version 99 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.