Biochemistry Chapter 5 - Membranes & Signal Transduction PDF

Chapter 5 Membranes and an Introduction to Signal Transduction Biochemistry First Edition John Tansey Lecture PowerPoints Tanea Reed/ Dr. Jose Sapien Chapter 5 Outline 5.1 Membrane structure and function 5.2 Signal transduction Copyright © 2019 John Wiley & Sons, Inc. Section 5.2 Learning Obje...

Chapter 5 Membranes and an Introduction to Signal Transduction Biochemistry First Edition John Tansey Lecture PowerPoints Tanea Reed/ Dr. Jose Sapien Chapter 5 Outline 5.1 Membrane structure and function 5.2 Signal transduction Copyright © 2019 John Wiley & Sons, Inc. Section 5.2 Learning Objective ▪ Diagram how signaling pathways act to regulate biological processes. Copyright © 2019 John Wiley & Sons, Inc. Cellular communication ▪ Cellular communication requires all of these important steps to occur: o Generation of signal (e.g. by a cell) o Reception of signal by target cell o Transduction of signal across target cell membrane o Response by target cell o Termination of signal Copyright © 2019 John Wiley & Sons, Inc. Signal Transduction (Cascade) ▪ Chemical signal binds to a receptor • Conformational change occurs. ▪ Second messenger is produced • Signal is amplified ▪ Activates or inhibits protein kinases Copyright © 2019 John Wiley & Sons, Inc. Signal Transduction Diagram Figure 5.8 Signal transduction fundamentals. Copyright © 2019 John Wiley & Sons, Inc. ▪ There are many advantages to this system: • It can be at once both general and highly specific. • One signal may have multiple different outcomes in different tissues, based on the types of receptor and downstream signaling pathways activated. • Multiple chemical signals may bind to a single receptor, eliciting the same response. • The multiple steps in these pathways provide multiple points at which the system can be controlled and finetuned, either by other proteins or through allosterism. Copyright © 2019 John Wiley & Sons, Inc. ▪ The multiple steps in these pathways provide multiple points at which the system can be controlled and finetuned, either by other proteins or through allosterism. Copyright © 2019 John Wiley & Sons, Inc. Protein Kinase A (PKA) ▪ It is also known as PKA, cAMP dependent protein kinase, or A-kinase signaling pathway ▪ Contains two catalytic and two regulatory subunits ▪ Regulatory subunits contain two cAMP binding sites ▪ Involved in several cellular pathways including: • lipolysis • glycogen metabolism • neurotransmission Copyright © 2019 John Wiley & Sons, Inc. PKA Signaling Pathway (1-2)Both the α and γ subunits are tethered to the plasma membrane by a lipid modification (3)The Gα subunit bound to GTP is now active, and it can associate with and activate the enzyme adenylate cyclase. Figure 5.9 PKA signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. PKA Signaling Pathway (4)Adenylate cyclase catalyzes the formation of cyclic AMP (cAMP) from ATP. This is an illustration of how signals can be amplified. A single G protein activates a single molecule of adenylate cyclase, but this enzyme can rapidly produce tens of thousands of molecules of cAMP. Figure 5.9 PKA signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. PKA Signaling Pathway (4)Adenylate cyclase catalyzes the formation of cyclic AMP (cAMP) from ATP. This is an illustration of how signals can be amplified. A single G protein activates a single molecule of adenylate cyclase, but this enzyme can rapidly produce tens of thousands of molecules of cAMP. Figure 5.9 PKA signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. PKA Signaling Pathway (5) PKA is a heterotetrameric enzyme complex comprised of a dimer of regulatory subunits found between two catalytic subunits. (four sites for cAMP binding in the holoenzyme complex) Figure 5.9 PKA signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. ▪ There are numerous ways in which this pathway is regulated. First, when GTP is hydrolyzed, the Gα subunit needs to reassociate with the Gβγ dimer and then to a ligand-bound receptor in order to reactivate. Copyright © 2019 John Wiley & Sons, Inc. Cholera Toxin: A G Protein Cascade Figure 5.10 Cholera toxin. Copyright © 2019 John Wiley & Sons, Inc. Copyright © 2019 John Wiley & Sons, Inc. Insulin ▪ Pancreatic hormone ▪ Plays an integral role in glucose metabolism and diabetes. It is also a growth factor and can affect gene expression. ▪ An example of a receptor tyrosine kinase Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway The insulin receptor is itself a kinase that phosphorylates tyrosine residues in the other copy found in the homodimer. This type of receptor is a receptor tyrosine kinase (RTK), a type of receptor architecture often found in growth factor signaling. Figure 5.11 Insulin signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway (2) The phosphorylated insulin receptor binds to and phosphorylates the insulin receptor substrate (IRS-1), which is a scaffolding protein. Scaffolding proteins act as a molecular framework that forms an assembly point for other proteins. Figure 5.11 Insulin signaling pathway. Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway (2b) activation of the Erk proteins of the MAP kinase cascade. This cascade ultimately affects gene expression, regulating cell growth and differentiation. OR (2a) the phosphoinositide or PI cascade. PI is a phospholipid found on the cytosolic face of the plasma membrane. One of the proteins that phosphorylated IRS recruits is phosphatidyl inositol-4,5-bis phosphate 3 kinase (PI3K). Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway (2b) activation of the Erk proteins of the MAP kinase cascade. This cascade ultimately affects gene expression, regulating cell growth and differentiation. OR (2a) the phosphoinositide or PI cascade. PI is a phospholipid found on the cytosolic face of the plasma membrane. One of the proteins that phosphorylated IRS recruits is phosphatidyl inositol-4,5-bis phosphate 3 kinase (PI3K). Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway (2a) Phosphatidylinositol is found in the lipid bilayer and has the polar alcohol inositol as its head group. Inositol has six different hydroxyl groups, each of which can be phosphorylated, and alterations to these are important in cellular signaling. The PI cascade is the series of enzymatic modifications that can occur to this phospholipid head group. Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway (3) PIP3 activates phosphoinositide dependent kinase 1 (PDK1), an enzyme that has several roles in the cell, and it acts in part to regulate cross talk between several signaling pathways. In this instance, however, PDK1 phosphorylates and activates the kinase Akt. Copyright © 2019 John Wiley & Sons, Inc. Insulin Signaling Pathway Akt phosphorylates several proteins in a complex that initiates the translocation and fusion of Glut4-coated vesicles to the plasma membrane. Glut4 is a glucose transporter. Therefore, stimulation of Akt via the insulin signaling cascade results in an increased number of glucose transporters being deposited in the plasma membrane, leading to increased glucose transport. Akt can also increase protein expression and production via a signaling cascade involving the protein complex mTOR. Copyright © 2019 John Wiley & Sons, Inc. Copyright © 2019 John Wiley & Sons, Inc. AMP Kinase ▪ Cytosolic kinase ▪ Activated by binding of AMP or phosphorylation by kinases ▪ Acts as an energy sensor ▪ Regulated by PKA, insulin, and calmodulin kinase kinase Copyright © 2019 John Wiley & Sons, Inc. AMP Kinase Signaling Pathway Figure 5.12 AMP kinase signaling. Copyright © 2019 John Wiley & Sons, Inc. Copyright Copyright © 2019 John Wiley & Sons, Inc. All rights reserved. Reproduction or translation of this work beyond that permitted in Section 117 of the 1976 United States Act without the express written permission of the copyright owner is unlawful. Request for further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. The purchaser may make back-up copies for his/her own use only and not for distribution or resale. 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