Johnson's Monday Lab Sandbox for Insulin Receptor

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Function of the Receptor

The insulin receptor serves as the gateway for regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, autophagy, apoptosis, and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer ^[3]. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.

Insulin

WHAT IS INSULIN. WHAT DOES IT LOOK LIKE? WHERE IS IT MADE? WHAT DOES IT DO? WHERE DOES IT GO? WHY DO WE NEED IT?

Structure

The insulin receptor is a heterotetramer which resides in the plasma membrane of insulin target cell. The ectodomain is made up of two alpha subunits and two beta subunits. Each alpha subunit contains two leucine-rich domains and a cysteine-rich domain. Each beta subunit is made up of three fibronectin type III domains. The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a transmembrane alpha helix. The intracellular domain contains two tyrosine kinase domains. NEED TO DISCUSS V VS T SHAPE. OVERLAPPING OF HOMODIMERS. C TERM ALPHA HELIX. COVALENT DISULFIDE BONDS

Insulin Binding

The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through hydrophobic interactions. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)^[4].

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation ^[4]. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound ^[4].

The insulin molecules in site 1 and 1' have their main interactions with an in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

Conformational Changes

STABLIZING INTERACTIONS. HOW DOES THE SHAPE CHANGE? WHEN IS CHANGE DRASTIC? NOT MUCH IS KNOWN ABOUT HOW THIS HAPPENS.

Type II Diabetes

WHAT IS T2D? HOW DOES IT RELATE TO THE INSULIN RECEPTOR? WHAT DOES A NON T2D SYSTEM LOOK LIKE? HOW DOES IT COMPARE TO T1D? WHY IS THIS IMPORTANT?

References

^{[5] [6] [3] [4]}

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
3. ↑ ^{3.0 3.1} Scapin G, Dandey VP, Zhang Z, Prosise W, Hruza A, Kelly T, Mayhood T, Strickland C, Potter CS, Carragher B. Structure of the Insulin Receptor-Insulin Complex by Single Particle CryoEM analysis. Nature. 2018 Feb 28. pii: nature26153. doi: 10.1038/nature26153. PMID:29512653 doi:http://dx.doi.org/10.1038/nature26153
4. ↑ ^{4.0 4.1 4.2 4.3} Uchikawa E, Choi E, Shang G, Yu H, Bai XC. Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex. Elife. 2019 Aug 22;8. pii: 48630. doi: 10.7554/eLife.48630. PMID:31436533 doi:http://dx.doi.org/10.7554/eLife.48630
5. ↑ Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014 Jan 1;6(1). pii: 6/1/a009191. doi:, 10.1101/cshperspect.a009191. PMID:24384568 doi:http://dx.doi.org/10.1101/cshperspect.a009191
6. ↑ De Meyts P. The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signalling. Diabetologia. 1994 Sep;37 Suppl 2:S135-48. doi: 10.1007/bf00400837. PMID:7821729 doi:http://dx.doi.org/10.1007/bf00400837

Student Contributors

• Maxwell Todd
• Abby Hillan
• Andrew Scheel