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Adenylyl Cyclase

Adenylyl Cyclase. Overview/Structure. What does it do?. Overview- General Structure. Lyase Enzyme that converts ATP to cAMP Interacts with g proteins and receptors 1064-1353 amino acids long 120-150 kilodaltons. General Structure cont’d. 10 mammalian isoforms All membrane bound

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Adenylyl Cyclase

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  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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