| Structural highlights
Disease
[INS_HUMAN] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730].[1] [2] [3] [4] Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.[5] Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:606176]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.[6] [7] Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:613370]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[8] [9] [10]
Function
[INS_HUMAN] 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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The structure of a symmetric T3R3f insulin hexamer, complexed with 4-hydroxybenzamide, has been determined using X-ray crystallographic techniques. Data were measured from six crystals grown in microgravity to a resolution of 1.4 A and the structure has been refined including the contributions from hydrogen atoms. The crystals are isomorphous with T3R3f complexes of phenolic derivatives as well as with uncomplexed forms. Unlike the structures of complexes with phenol, m-cresol, resorcinol, 4'-hydroxyacetanilide, and methylparaben, which bind one phenolic derivative molecule per R- or Rf-state monomer, two molecules of 4-hydroxybenzamide are bound by each Rf-state monomer. The presence of the second guest molecule results in an extensive hydrogen bonding network, mediated by water molecules, between the T- and Rf-state trimers and adds stability to the formation of the hexamer. The only access to these second sites is through three symmetry-related, narrow channels that originate on the surface of the T-state trimer. Although the conformation of the backbone atoms of the monomers is nearly identical to that of other T3R3f hexamers, significant changes are observed in the conformations of side chains in the vicinity of the second binding site. The side chain of the T-state A11 Cys residue, which forms a disulfide bond to A6 Cys in the same monomer, is observed in two discrete conformations; two discrete conformations are also present for the entire A8 Thr residue in the Rf-state monomer. A procedure is also described for an alternate method of interframe scaling and merging intensity data from an image plate detector.
A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition.,Smith GD, Ciszak E, Pangborn W Protein Sci. 1996 Aug;5(8):1502-11. PMID:8844841[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chan SJ, Seino S, Gruppuso PA, Schwartz R, Steiner DF. A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2194-7. PMID:3470784
- ↑ Barbetti F, Raben N, Kadowaki T, Cama A, Accili D, Gabbay KH, Merenich JA, Taylor SI, Roth J. 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. J Clin Endocrinol Metab. 1990 Jul;71(1):164-9. PMID:2196279
- ↑ Shibasaki Y, Kawakami T, Kanazawa Y, Akanuma Y, Takaku F. Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia. J Clin Invest. 1985 Jul;76(1):378-80. PMID:4019786 doi:http://dx.doi.org/10.1172/JCI111973
- ↑ Yano H, Kitano N, Morimoto M, Polonsky KS, Imura H, Seino Y. A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto). J Clin Invest. 1992 Jun;89(6):1902-7. PMID:1601997 doi:http://dx.doi.org/10.1172/JCI115795
- ↑ Molven A, Ringdal M, Nordbo AM, Raeder H, Stoy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Sovik O, Bell GI, Njolstad PR. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008 Apr;57(4):1131-5. doi: 10.2337/db07-1467. Epub 2008 Jan 11. PMID:18192540 doi:10.2337/db07-1467
- ↑ Stoy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15040-4. Epub 2007 Sep 12. PMID:17855560 doi:10.1073/pnas.0707291104
- ↑ Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Stoy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008 Apr;57(4):1034-42. Epub 2007 Dec 27. PMID:18162506 doi:10.2337/db07-1405
- ↑ Molven A, Ringdal M, Nordbo AM, Raeder H, Stoy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Sovik O, Bell GI, Njolstad PR. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008 Apr;57(4):1131-5. doi: 10.2337/db07-1467. Epub 2008 Jan 11. PMID:18192540 doi:10.2337/db07-1467
- ↑ Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Stoy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008 Apr;57(4):1034-42. Epub 2007 Dec 27. PMID:18162506 doi:10.2337/db07-1405
- ↑ Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J, Damm P, Bergholdt R, Pociot F, Pisinger C, Barbetti F, Lebl J, Pedersen O, Hansen T. Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY). BMC Med Genet. 2010 Mar 12;11:42. doi: 10.1186/1471-2350-11-42. PMID:20226046 doi:10.1186/1471-2350-11-42
- ↑ Smith GD, Ciszak E, Pangborn W. A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition. Protein Sci. 1996 Aug;5(8):1502-11. PMID:8844841
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