Phosphoinositide 3-kinase structure

Table 4.1 Summary of the structural properties of the three classes of phosphoinositide kinases (PI 3-kinases) and their substrates...

Wymann, M. P. and Pirola, L., Structure and function of phosphoinositide 3-kinases, Biochim. Biophys. Acta, 1436, 127-150, 1998. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP. 2000. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6 909-919. 

With its multiple second messengers and protein kinases, the phosphoinositide signaling pathway is much more complex than the cAMP pathway. For example, different cell types may contain one or more specialized calcium- and calmodulin-dependent kinases with limited substrate specificity (eg, myosin light chain kinase) in addition to a general calcium- and calmodulin-dependent kinase that can phosphorylate a wide variety of protein substrates. Furthermore, at least nine structurally distinct types of protein kinase C have been identified. 

Alessi, D.R., Deak, M., Casamayor, A., Caudwell, F.B., Morrice, N., Norman, D.G., Gaffney, P., Reese, C.B., MacDougall, C.N., Harbison, D., et al. (1997). 3-Phosphoinositide-dependent protein kinase-1 (PDK1) structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 7, 776-789. 

Figure 14.21 The modular structure of Insulin receptor substrates IRS-1 and IRS-2 This schematic view represents the amino acid sequence common to IRS-1 and lRS-2. Each protein contains a pleckstrin homology domain (which binds phosphoinositide lipids), a phospbotyrosine-binding domain, and four sequences that approximate Tyr-X-X-Met (YXXM). The latter are phosphorylated by the insulin receptor tyrosine kinase.

Fig. 12. Some signaling targets and pathways affected by sphingolipid backbones that are metabolically interrelated. PKA, protein kinase A PDKl, 3-phosphoinositide-dependent kinase 1 SDKl, sphingosine-dependent kinase 1 PKC, protein kinase C PPl, protein phosphatase 1 PP2A, protein phosphatase 2A aSMase, acid sphingomyelinase PLA, phospholipase Aj SIP, sphingosine-l-phosphase MATIA, methionine adenosyl-transferase (liver specific) SFl, steroidogenic factor 1. The biophysical properties of ceramides and ceramide 1-phosphates may play important roles in membrane structure, including tendencies to form rafts, membrane curvature, and leakiness.

Musacchio, A., Cantley, L. C., and Harrison, S. C. (1996). Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. Proc. Natl. Acad. Sci. USA 93, 14373-14378. 

Figure 1.23 The structure of staurosporine (a), as a robust, nonselective kinase inhibitor, and wortmannin (b), a highly specific phosphoinositide 3-kinase inhibitor.

Figure 1. Structure of phosphatidylinositol. Phosphatidylinositol (Ptdins) constitutes about 10% of the total phospholipids in eukaryotic cells and is the precursor of the other phosphoinositides (polyphosphoinositides) through sequential phosphorylations by specific kinases. As indicated, its inositol head group can be phosphorylated at three positions (D-3, D-4 and D-5) by specific kinases in vivo. The cleavage by phosphoinositide-specific phospholipase C (PLC), which has as its preferred substrate PtdIns(4,5)P2, is also shown. PI3K, phosphoinositide 3-kinase. PI-K II and III, phosphatidylinositol kinase types II and III. PIP-K I, phosphatidylinositol monophosphate kinase type I. PIP-K II, phosphatidylinositol monophosphate kinase type II.

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