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Adenylyl Cyclase

Learn about the overview, structure, and functions of adenylyl cyclase, an enzyme crucial in signal transduction converting ATP to cAMP. Discover the primary, secondary, tertiary, and quaternary structure, its interaction with G proteins, activation mechanisms, and regulatory pathways by receptors and ions. References to explore further are provided.

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Adenylyl Cyclase

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Presentation Transcript

  1. Adenylyl Cyclase Overview/Structure

  2. What does it do?

  3. Overview- General Structure • Lyase • Enzyme that converts ATP to cAMP • Interacts with g proteins and receptors • 1064-1353 amino acids long • 120-150 kilodaltons

  4. General Structure cont’d • 10 mammalian isoforms • All membrane bound • 60% similarity • 50%-90% in cytoplasmic regions

  5. Primary Structure • The main structural features of mammalian adenylyl cyclases • M1/M2: 2 sets 6 transmembrane spans • C1a/C1b: large cytoplamic domains (360-390 amino acids) • C2a/C2b: large cytoplasmic domains (255-330 amino acids) • Most highly conserved sequence in all isoforms • 50% similar; 25% identical • N terminus and C terminus

  6. Primary Structure Topology

  7. Secondary Structure • Alpha helices • Beta sheets

  8. Tertiary Structure • The folding of a protein into a 3-D structure

  9. Quaternary Structure • Interaction between two domains • Large cytoplasmic domains • C1a • C2b

  10. Quaternary Structure • Adenylyl cyclase interaction with G protein

  11. Adenylyl Cyclase Function

  12. Overview Signal Transduction -produces cyclic AMP from ATP -responds to a large number of receptors 10 Isoforms -allows a diverse response to the same or similar signals

  13. Overview sAC is the tenth form of AC. It is soluble and only found in sperm

  14. Activation Forskolin - increases affinity - increases stability - enhances activity Forskolin

  15. Activation

  16. Activation

  17. Activation

  18. Catalysis Mechanism ATP → cAMP +PPi → + ATP cAMP pyrophosphate

  19. Catalysis Mechanism

  20. Catalysis Mechanism

  21. Role of Cyclic AMP Step 1: activates protein kinases Step 2: protein kinases phosphorylate substrate proteins Step 3: activated substrate proteins regulate hormone production

  22. Adenylyl CyclaseRegulation

  23. ADENYLYL CYCLASE RECEPTOR GDP GTP

  24. Regulation by Receptors Alpha-adrenergic receptors: - Stimulate Gi Proteins Beta-adrenergic receptors: - Stimulate Gs Proteins G Protein Coupled Receptor

  25. G PROTEIN REGULATION(Guanine Nucleotide-Binding Protein)

  26. ADENYLYL CYCLASE BINDING

  27. Ca2+ Regulation Site

  28. CALCIUM/CALMODULIN CA2+ ions CALMODULIN

  29. PKC(Protein Kinase C)

  30. References The University of Oklahoma College of Medicine. Human Physiology Animations Page http://w3.ouhsc.edu/human_physiology/presentation/cyclaseani.gif (movie) Western Kentucky University: Advanced Molecular Genetics http://bioweb.wku.edu/courses/ biol566/Images/gp009.jpg (both primary pics) Saint Edward’s University. Structure of G-Proteins and Adenylyl Cyclases. http://www.cs.stedwards.edu Hanoune, Jacques, et al. Adenylyl cyclases: structure, regulation and function in an enzyme superfamily. Molecular and Cellular Endocrinology 1997: (128) 179-194. Tang, Wei-Jen and James Hurley. Catalytic Mechanism and Regulation of Mammalian Adenylyl Cyclases. Molecular Pharmacology 1998: (54) 231-240. Sunahara, Roger et al. Complexity and Diversity of Mammalian Adenylyl Cyclases. Annual Review of Pharmacology Toxicology 1996: (36) 461-480. Cann, Martin. Bicarbonate Stimulated Adenylyl Cyclases. Life 2004: (9) 529-534.

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