Johnson's Monday Lab Sandbox for Insulin Receptor
From Proteopedia
Insulin Receptor
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Function of the ReceptorThe insulin receptor resides within the plasma membrane of insulin targeted cells of various organs and tissues, including the liver, skeletal muscle, and adipose. The insulin receptor is activated by insulin molecules binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, autophagy, apoptosis, and gene expression. Additionally, problems with 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 the disease. Insulin StructureThe insulin receptor is a receptor tyrosine kinase. It is a heterotetramer that is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The insulin is divided into subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine-rich region. The beta subunit contains three fibronectin type III domains along with the transmembrane domain and intracellular tyrosine kinase domain that could not be shown in one continous PDB structure. The alpha and beta subunits of the extracellular domains fold over one another and form a when the insulin receptor is inactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a .  An additional component to the ectodomain is the , which is also referred to as the "alpha-CT" [4]. The alpha-CT is a single alpha-helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The alpha-CT interacts with a leucine-rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form the insulin binding sites known as site 1 and site 1' [4]. The structure of the extracellular domain is stabilized through covalent bonds. The alpha subunits are linked through two disulfide bonds, with the main one being between of one alpha subunit and of the other alpha subunit [5]. of both alpha subunits hold the two together with a disulfide bond [6]. The alpha subunit is held to the beta subunit by a disulfide bond between the [6]. The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a transmembrane helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains. Insulin BindingThe insulin receptor unit has four separate sites for the insulin binding. There are two pairs of two identical binding sites referred to as sites 1 and 1' and sites 2 and 2'. The insulin molecules bind to these sites mostly through hydrophobic interactions, with some of the most crucial residues at sites 1 and 1' being between of the insulin receptor FnIII-1 domain [4]. Despite some of the residues included being charged they can still interact hydrophobically in this binding site. For example, due to arginine carrying its positive charge at the end of the side chain, to allow the hydrophobic part of the side chain to interact with the other hydrophobic residues. At sites 2 and 2', the major residues contributing to these hydrophobic interactions are the [4]. While the majority of the binding interactions appear similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site 1 having a larger surface area (706 Å2) exposed for insulin to bind to compared to site 2 (394 Å2)[4]. The binding interactions of the insulin molecules in sites 1 and 1' are facilitated by hydrophobic residues of an of the insulin receptor. The insulin molecules in sites 2 and 2' primarily interact with the residues that comprise some of the of the insulin receptor. The secondary structures themselves are not what directly causes the differences in binding affinities, but the surface area that the insulin molecule can interact with. At least three insulin molecules have to bind to the insulin receptor to induce the active 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]. However, binding only two insulin molecules is insufficient to move the receptor to the active "T" shape [4]. Conformational Changes The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the of the beta subunit is initiated. This is accomplished by the formation of several salt bridges, specifically between [4]. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion [4] as both protomers "swing" in towards one another. As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine-rich region of one protomer interacts with the alpha-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface [4]. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion. While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for the mechanism by which the conformational changes are executed [4]. Type II DiabetesType II Diabetes is a chronic condition that affects 415 million people worldwide. It is characterized by insulin resistance and leads to high concentrations of glucose in the bloodstream. A type II diabetic produces insulin, but when the insulin molecule binds to the insulin receptor, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. However, the reason why the signal is not processed remains largely unknown. Current hypotheses suspect that insulin resistance results from a loss of signal during intracellular transduction [7]. Potential explanations for loss of function include, but are not limited to, a sedentary lifestyle, high caloric intake, genetics, gestational environment, and microbiome, [8]. It is unlikely that insulin resistance is a consequence of insulin receptor function failure, as the insulin receptor is pivotal in many cellular functions such as gene expression. Loss of function of the insulin receptor would likely be fatal. Both type II and type I diabetes are chronic conditions. However, type I is an autoimmune disease that affects insulin secretion into the bloodstream. The result is increased concentrations of glucose in the bloodstream. This is different for type II diabetics as they produce insulin, but the cells in the body are unable to properly respond to the signal of insulin binding. References
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