Understanding Insulin and Its Receptor from Their Three-dimensional Structures

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2021 May 16

PMID 33992784

Citations 43

Authors

Michael C Lawrence

Affiliations

Soon will be listed here.

Abstract

Background: Insulin's discovery 100 years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor. Advances in single-particle cryo-electron microscopy have over the past three years revolutionized our understanding of the atomic detail of insulin-receptor interactions.

Scope Of Review: This review describes the three-dimensional structure of insulin and its receptor and details on how they interact. This review also highlights the current gaps in our structural understanding of the system.

Major Conclusions: A near-complete picture has been obtained of the hormone receptor interactions, providing new insights into the kinetics of the interactions and necessitating a revision of the extant two-site cross-linking model of hormone receptor engagement. How insulin initially engages the receptor and the receptor's traversed trajectory as it undergoes conformational changes associated with activation remain areas for future investigation.

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References

Shoelson S, Lee J, Lynch C, Backer J, Pilch P . BpaB25 insulins. Photoactivatable analogues that quantitatively cross-link, radiolabel, and activate the insulin receptor. J Biol Chem. 1993; 268(6):4085-91. View

Huang K, Chan S, Hua Q, Chu Y, Wang R, Klaproth B . The A-chain of insulin contacts the insert domain of the insulin receptor. Photo-cross-linking and mutagenesis of a diabetes-related crevice. J Biol Chem. 2007; 282(48):35337-49. DOI: 10.1074/jbc.M705996200. View

Nakagawa S, Tager H . Role of the phenylalanine B25 side chain in directing insulin interaction with its receptor. Steric and conformational effects. J Biol Chem. 1986; 261(16):7332-41. View

Tavare J, OBrien R, Siddle K, Denton R . Analysis of insulin-receptor phosphorylation sites in intact cells by two-dimensional phosphopeptide mapping. Biochem J. 1988; 253(3):783-8. PMC: 1149371. DOI: 10.1042/bj2530783. View

Derewenda U, Derewenda Z, Dodson E, Dodson G, Bing X, Markussen J . X-ray analysis of the single chain B29-A1 peptide-linked insulin molecule. A completely inactive analogue. J Mol Biol. 1991; 220(2):425-33. DOI: 10.1016/0022-2836(91)90022-x. View

Adams T, Epa V, Garrett T, Ward C . Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci. 2000; 57(7):1050-93. PMC: 11146944. DOI: 10.1007/PL00000744. View

Bentley G, Brange J, Derewenda Z, Dodson E, Dodson G, Markussen J . Role of B13 Glu in insulin assembly. The hexamer structure of recombinant mutant (B13 Glu-->Gln) insulin. J Mol Biol. 1992; 228(4):1163-76. DOI: 10.1016/0022-2836(92)90323-c. View

Marino-Buslje C, Mizuguchi K, Siddle K, Blundell T . A third fibronectin type III domain in the extracellular region of the insulin receptor family. FEBS Lett. 1999; 441(2):331-6. DOI: 10.1016/s0014-5793(98)01509-9. View

Schaffer L, Ljungqvist L . Identification of a disulfide bridge connecting the alpha-subunits of the extracellular domain of the insulin receptor. Biochem Biophys Res Commun. 1992; 189(2):650-3. DOI: 10.1016/0006-291x(92)92250-2. View

10.

Nanjo K, Sanke T, Miyano M, Okai K, Sowa R, Kondo M . Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin. J Clin Invest. 1986; 77(2):514-9. PMC: 423373. DOI: 10.1172/JCI112331. View

11.

Hua Q, Shoelson S, Inouye K, Weiss M . Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus. Proc Natl Acad Sci U S A. 1993; 90(2):582-6. PMC: 45707. DOI: 10.1073/pnas.90.2.582. View

12.

SANGER F, Tuppy H . The amino-acid sequence in the phenylalanyl chain of insulin. 2. The investigation of peptides from enzymic hydrolysates. Biochem J. 1951; 49(4):481-90. PMC: 1197536. DOI: 10.1042/bj0490481. View

13.

De Meyts P . Insulin and its receptor: structure, function and evolution. Bioessays. 2004; 26(12):1351-62. DOI: 10.1002/bies.20151. View

14.

Williams P, Mynarcik D, Yu G, Whittaker J . Mapping of an NH2-terminal ligand binding site of the insulin receptor by alanine scanning mutagenesis. J Biol Chem. 1995; 270(7):3012-6. DOI: 10.1074/jbc.270.7.3012. View

15.

Schaffer L . A model for insulin binding to the insulin receptor. Eur J Biochem. 1994; 221(3):1127-32. DOI: 10.1111/j.1432-1033.1994.tb18833.x. View

16.

Souza P, Limongelli V, Wu S, Marrink S, Monticelli L . Perspectives on High-Throughput Ligand/Protein Docking With Martini MD Simulations. Front Mol Biosci. 2021; 8:657222. PMC: 8039319. DOI: 10.3389/fmolb.2021.657222. View

17.

Kasuga M, Hedo J, Yamada K, Kahn C . The structure of insulin receptor and its subunits. Evidence for multiple nonreduced forms and a 210,000 possible proreceptor. J Biol Chem. 1982; 257(17):10392-9. View

18.

Frattali A, TREADWAY J, Pessin J . Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular beta subunit trans- and cis-autophosphorylation and substrate kinase activation. J Biol Chem. 1992; 267(27):19521-8. View

19.

Lawrence C, Margetts M, Menting J, Smith N, Smith B, Ward C . Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor. J Biol Chem. 2016; 291(30):15473-81. PMC: 4957034. DOI: 10.1074/jbc.M116.732180. View

20.

Lou M, Garrett T, McKern N, Hoyne P, Epa V, Bentley J . The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity. Proc Natl Acad Sci U S A. 2006; 103(33):12429-34. PMC: 1533800. DOI: 10.1073/pnas.0605395103. View