Reviewed, UniProtKB/Swiss-Prot P01308 (INS_HUMAN)

Names and origin

Protein names

Recommended name:
    Insulin
Cleaved into the following 2 chains:
    1- Recommended name:
            Insulin B chain
    2- Recommended name:
            Insulin A chain

Gene names

Name:

INS

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	110 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
Subunit structure	Heterodimer of a B chain and an A chain linked by two disulfide bonds.
Subcellular location	Secreted.
Involvement in disease	Defects in INS are the cause of familial hyperproinsulinemia [MIM:176730].
Pharmaceutical use	Available under the names Humulin or Humalog (Eli Lilly) and Novolin (Novo Nordisk). Used in the treatment of diabetes. Humalog is an insulin analog with 52-Lys-Pro-53 instead of 52-Pro-Lys-53.
Sequence similarities	Belongs to the insulin family.
Sequence caution	The sequence AAA59179.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Carbohydrate metabolism Glucose metabolism
Cellular component	Secreted
Disease	Diabetes mellitus Disease mutation
Domain	Signal
Molecular function	Hormone
PTM	Cleavage on pair of basic residues
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological process	G-protein coupled receptor protein signaling pathway Inferred from direct assay. Source: UniProtKB acute-phase response Inferred from direct assay. Source: UniProtKB alpha-beta T cell activation Inferred from direct assay. Source: UniProtKB cell death Non-traceable author statement. Source: UniProtKB cell-cell signaling Inferred by curator. Source: UniProtKB fatty acid homeostasis Inferred from mutant phenotype. Source: UniProtKB glucose homeostasis Inferred from mutant phenotype. Source: UniProtKB negative regulation of NAD(P)H oxidase activity Inferred from direct assay. Source: UniProtKB negative regulation of acute inflammatory response Inferred from direct assay. Source: UniProtKB negative regulation of fatty acid metabolic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of glycogen catabolic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of protein catabolic process Inferred from direct assay. Source: UniProtKB negative regulation of protein secretion Inferred from direct assay. Source: UniProtKB negative regulation of proteolysis Inferred from mutant phenotype. Source: UniProtKB negative regulation of respiratory burst during acute inflammatory response Inferred from direct assay. Source: UniProtKB negative regulation of vasodilation Non-traceable author statement. Source: UniProtKB phosphoinositide 3-kinase cascade Inferred from direct assay. Source: UniProtKB positive regulation of DNA replication Inferred from direct assay. Source: UniProtKB positive regulation of cellular protein metabolic process Inferred from mutant phenotype. Source: UniProtKB positive regulation of cytokine secretion Inferred from direct assay. Source: UniProtKB positive regulation of glucose import Inferred from direct assay. Source: UniProtKB positive regulation of glycolysis Inferred from direct assay. Source: UniProtKB positive regulation of insulin receptor signaling pathway Inferred from direct assay. Source: UniProtKB positive regulation of nitric oxide biosynthetic process Non-traceable author statement. Source: UniProtKB positive regulation of nitric-oxide synthase activity Non-traceable author statement. Source: UniProtKB positive regulation of respiratory burst Non-traceable author statement. Source: UniProtKB positive regulation of vasodilation Non-traceable author statement. Source: UniProtKB regulation of amino acid metabolic process Inferred from mutant phenotype. Source: UniProtKB regulation of gene-specific transcription Non-traceable author statement. Source: UniProtKB regulation of protein localization Inferred from direct assay. Source: UniProtKB regulation of transmembrane transporter activity Inferred from direct assay. Source: UniProtKB wound healing Inferred from direct assay. Source: UniProtKB
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB
Molecular function	hormone activity Non-traceable author statement. Source: UniProtKB insulin receptor binding Inferred from direct assay. Source: UniProtKB insulin-like growth factor binding Inferred from physical interaction. Source: UniProtKB insulin-like growth factor receptor binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 24

24

Peptide

25 – 54

30

Insulin B chain

Propeptide

57 – 87

31

C peptide

Peptide

90 – 110

21

Insulin A chain

Amino acid modifications

Disulfide bond

31 ↔ 96

Interchain (between B and A chains)

Disulfide bond

43 ↔ 109

Interchain (between B and A chains)

Disulfide bond

95 ↔ 100

Natural variations

Natural variant

34

1

H → D in familial hyperproinsulinemia; Providence.

Natural variant

48

1

F → S Associated with diabetes mellitus type-II; Los-Angeles.

Natural variant

49

1

F → L in Chicago.

Natural variant

89

1

R → H in familial hyperproinsulinemia; impairs posttranslational cleavage.

Natural variant

89

1

R → L in familial hyperproinsulinemia; Kyoto.

Natural variant

92

1

V → L in Wakayama.

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

110

Helix Strand Turn

Details...

Helix

33 – 43

11

Helix

44 – 46

3

Beta strand

48 – 50

3

Turn

61 – 66

6

Beta strand

74 – 76

3

Helix

79 – 81

3

Turn

84 – 86

3

Helix

91 – 95

5

Helix

102 – 105

4

Helix

106 – 108

3

Sequences

	Sequence		Length	Mass (Da)
	P01308-1 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: C2C3B23B85E520E5	FASTA	110	11,981
	10 20 30 40 50 60 MALWMRLLPL LALLALWGPD PAAAFVNQHL CGSHLVEALY LVCGERGFFY TPKTRREAED 70 80 90 100 110 LQVGQVELGG GPGAGSLQPL ALEGSLQKRG IVEQCCTSIC SLYQLENYCN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence of the human insulin gene." Bell G.I., Pictet R.L., Rutter W.J., Cordell B., Tischer E., Goodman H.M. Nature 284:26-32(1980) [PubMed: 6243748] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Genetic variation in the human insulin gene." Ullrich A., Dull T.J., Gray A., Brosius J., Sures I. Science 209:612-615(1980) [PubMed: 6248962] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Nucleotide sequence of a cDNA clone encoding human preproinsulin." Bell G.I., Swain W.F., Pictet R.L., Cordell B., Goodman H.M., Rutter W.J. Nature 282:525-527(1979) [PubMed: 503234] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Nucleotide sequence of human preproinsulin complementary DNA." Sures I., Goeddel D.V., Gray A., Ullrich A. Science 208:57-59(1980) [PubMed: 6927840] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR." Lucassen A.M., Julier C., Beressi J.-P., Boitard C., Froguel P., Lathrop M., Bell J.I. Nat. Genet. 4:305-310(1993) [PubMed: 8358440] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Insulinomas and expression of an insulin splice variant." Minn A.H., Kayton M., Lorang D., Hoffmann S.C., Harlan D.M., Libutti S.K., Shalev A. Lancet 363:363-367(2004) [PubMed: 15070567] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[7]	"Global haplotype diversity in the human insulin gene region." Stead J.D.H., Hurles M.E., Jeffreys A.J. Genome Res. 13:2101-2111(2003) [PubMed: 12952878] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"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 (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[9]	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].
[10]	"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: Pancreas.
[11]	"Description of a novel RFLP diallelic polymorphism (-127 BsgI C/G) within the 5' region of insulin gene." Fajardy I.I., Weill J.J., Stuckens C.C., Danze P.M.P. Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-59. Tissue: Blood.
[12]	"Amino-acid sequence of human insulin." Nicol D.S.H.W., Smith L.F. Nature 187:483-485(1960) [PubMed: 14426955] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-54 AND 90-110.
[13]	"Studies on human proinsulin. Isolation and amino acid sequence of the human pancreatic C-peptide." Oyer P.E., Cho S., Peterson J.D., Steiner D.F. J. Biol. Chem. 246:1375-1386(1971) [PubMed: 5101771] [Abstract] Cited for: PROTEIN SEQUENCE OF 57-87.
[14]	"The amino acid sequence of the C-peptide of human proinsulin." Ko A., Smyth D.G., Markussen J., Sundby F. Eur. J. Biochem. 20:190-199(1971) [PubMed: 5560404] [Abstract] Cited for: PROTEIN SEQUENCE OF 57-87.
[15]	"Total synthesis of human insulin under directed formation of the disulfide bonds." Sieber P., Kamber B., Hartmann A., Joehl A., Riniker B., Rittel W. Helv. Chim. Acta 57:2617-2621(1974) [PubMed: 4443293] [Abstract] Cited for: SYNTHESIS.
[16]	"Studies on polypeptides, IV. The synthesis of C-peptide of human proinsulin." Naithani V.K. Hoppe-Seyler's Z. Physiol. Chem. 354:659-672(1973) [PubMed: 4803504] [Abstract] Cited for: SYNTHESIS OF 57-87.
[17]	"Synthesis of peptides with the properties of human proinsulin C peptides (hC peptide). 3. Synthesis of the sequences 14-17 and 9-13 of human proinsulin C peptides." Geiger R., Volk A. Chem. Ber. 106:199-205(1973) [PubMed: 4698555] [Abstract] Cited for: SYNTHESIS OF 65-69 AND 70-73.
[18]	"Synthesis of peptides with the properties of human proinsulin C peptides (hC peptide). I. Scheme for the synthesis and preparation of the sequence 28-31 of human proinsulin C peptide." Geiger R., Jaeger G., Keonig W., Treuth G. Chem. Ber. 106:188-192(1973) [PubMed: 4698553] [Abstract] Cited for: SYNTHESIS OF 84-87.
[19]	"Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding [SerB24]insulin." Haneda M., Chan S.J., Kwok S.C.M., Rubenstein A.H., Steiner D.F. Proc. Natl. Acad. Sci. U.S.A. 80:6366-6370(1983) [PubMed: 6312455] [Abstract] Cited for: VARIANT LOS ANGELES SER-48.
[20]	"Identification of a mutant human insulin predicted to contain a serine-for-phenylalanine substitution." Shoelson S., Fickova M., Haneda M., Nahum A., Musso G., Kaiser E.T., Rubenstein A.H., Tager H. Proc. Natl. Acad. Sci. U.S.A. 80:7390-7394(1983) [PubMed: 6424111] [Abstract] Cited for: VARIANTS LOS ANGELES SER-48 AND CHICAGO LEU-49.
[21]	"A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia." Chan S.J., Seino S., Gruppuso P.A., Schwartz R., Steiner D.F. Proc. Natl. Acad. Sci. U.S.A. 84:2194-2197(1987) [PubMed: 3470784] [Abstract] Cited for: VARIANT PROVIDENCE ASP-34.
[22]	"Structurally abnormal insulin in a diabetic patient. Characterization of the mutant insulin A3 (Val-->Leu) isolated from the pancreas." Sakura H., Iwamoto Y., Sakamoto Y., Kuzuya T., Hirata H. J. Clin. Invest. 78:1666-1672(1986) [PubMed: 3537011] [Abstract] Cited for: VARIANT WAKAYAMA LEU-92.
[23]	"Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction." Barbetti F., Raben N., Kadowaki T., Cama A., Accili D., Gabbay K.H., Merenich J.A., Taylor S.I., Roth J. J. Clin. Endocrinol. Metab. 71:164-169(1990) [PubMed: 2196279] [Abstract] Cited for: VARIANT HIS-89.
[24]	"Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia." Shibasaki Y., Kawakami T., Kanazawa Y., Akanuma Y., Takaku F. J. Clin. Invest. 76:378-380(1985) [PubMed: 4019786] [Abstract] Cited for: VARIANT HIS-89.
[25]	"A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto)." Yano H., Kitano N., Morimoto M., Polonsky K.S., Imura H., Seino Y. J. Clin. Invest. 89:1902-1907(1992) [PubMed: 1601997] [Abstract] Cited for: VARIANT KYOTO LEU-89.
[26]	"Toward the solution structure of human insulin: sequential 2D 1H NMR assignment of a des-pentapeptide analogue and comparison with crystal structure." Hua Q.-X., Weiss M.A. Biochemistry 29:10545-10555(1990) [PubMed: 2271664] [Abstract] Cited for: STRUCTURE BY NMR.
[27]	"Comparative 2D NMR studies of human insulin and des-pentapeptide insulin: sequential resonance assignment and implications for protein dynamics and receptor recognition." Hua Q.-X., Weiss M.A. Biochemistry 30:5505-5515(1991) [PubMed: 2036420] [Abstract] Cited for: STRUCTURE BY NMR.
[28]	"Two-dimensional NMR studies of Des-(B26-B30)-insulin: sequence-specific resonance assignments and effects of solvent composition." Hua Q.-X., Weiss M.A. Biochim. Biophys. Acta 1078:101-110(1991) [PubMed: 1646635] [Abstract] Cited for: STRUCTURE BY NMR.
[29]	"Three-dimensional solution structure of an insulin dimer. A study of the B9(Asp) mutant of human insulin using nuclear magnetic resonance, distance geometry and restrained molecular dynamics." Joergensen A.M.M., Kristensen S.M., Led J.J., Balschmidt P. J. Mol. Biol. 227:1146-1163(1992) [PubMed: 1433291] [Abstract] Cited for: STRUCTURE BY NMR.
[30]	"Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus." Hua Q.-X., Shoelson S.E., Inouye K., Weiss M.A. Proc. Natl. Acad. Sci. U.S.A. 90:582-586(1993) [PubMed: 8421693] [Abstract] Cited for: STRUCTURE BY NMR OF VARIANT LOS-ANGELES SER-48.
[31]	"Solution structures of the R6 human insulin hexamer." Chang X., Joergensen A.M., Bardrum P., Led J.J. Biochemistry 36:9409-9422(1997) [PubMed: 9235985] [Abstract] Cited for: STRUCTURE BY NMR.
+	Additional computationally mapped references.

Web resources

Insulin at Eli Lilly

Clinical information on Eli Lilly insulin products

Protein Spotlight

Protein of the 20th century - Issue 9 of April 2001

Wikipedia

Insulin entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

V00565 Genomic DNA. Translation: CAA23828.1.
M10039 Genomic DNA. Translation: AAA59173.1.
J00265 Genomic DNA. Translation: AAA59172.1.
X70508 mRNA. Translation: CAA49913.1.
L15440 Genomic DNA. Translation: AAA59179.1. Sequence problems.
AY899304 mRNA. Translation: AAW83741.1.
AY138590 Genomic DNA. Translation: AAN39451.1.
BT006808 mRNA. Translation: AAP35454.1.
CH471158 Genomic DNA. Translation: EAX02488.1.
BC005255 mRNA. Translation: AAH05255.1.
AJ009655 Genomic DNA. Translation: CAA08766.1.

PIR

IPHU. A93222.

RefSeq

NP_000198.1.

UniGene

Hs.654579

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A7F	NMR	-	A	90-110	[»]
			B	25-53	[»]
1AI0	NMR	-	A/C/E/G/I/K	90-110	[»]
			B/D/F/H/J/L	25-54	[»]
1AIY	NMR	-	A/C/E/G/I/K	90-110	[»]
			B/D/F/H/J/L	25-54	[»]
1B9E	X-ray	2.50	A/C	90-110	[»]
			B/D	25-54	[»]
1BEN	X-ray	1.40	A/C	90-110	[»]
			B/D	25-54	[»]
1EFE	NMR	-	A	25-60	[»]
1EV3	X-ray	1.78	A/C	90-110	[»]
			B/D	25-54	[»]
1EV6	X-ray	1.90	A/C/E/G/I/K	90-110	[»]
			B/D/F/H/J/L	25-54	[»]
1EVR	X-ray	1.90	A/C/E/G/I/K	90-110	[»]
			B/D/F/H/J/L	25-54	[»]
1FU2	X-ray	3.24	A/C/E/G	90-110	[»]
			B/D/F/H	25-54	[»]
1FUB	X-ray	3.09	A/C	90-110	[»]
			B/D	25-54	[»]
1G7A	X-ray	1.20	A/C/E/G	90-110	[»]
			B/D/F/H	25-54	[»]
1G7B	X-ray	1.30	A/C/E/G	90-110	[»]
			B/D/F/H	25-54	[»]
1GUJ	X-ray	1.62	A/C	90-110	[»]
			B/D	25-54	[»]
1HIQ	NMR	-	A	90-110	[»]
			B	25-54	[»]
1HIS	NMR	-	A	90-110	[»]
			B	25-49	[»]
1HIT	NMR	-	A	90-110	[»]
			B	25-54	[»]
1HLS	NMR	-	A	90-110	[»]
			B	25-54	[»]
1HTV	X-ray	1.90	A/C/E/G/I/K	90-110	[»]
			B/D/F/H/J/L	25-51	[»]
1HUI	NMR	-	A	90-110	[»]
			B	26-53	[»]
1IOG	NMR	-	A	90-110	[»]
			B	26-53	[»]
1IOH	NMR	-	A	90-110	[»]
			B	26-53	[»]
1J73	X-ray	2.00	A/C	90-110	[»]
			B/D	25-54