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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 Overview/Structure
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 • 60% similarity • 50%-90% in cytoplasmic regions
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
Secondary Structure • Alpha helices • Beta sheets
Tertiary Structure • The folding of a protein into a 3-D structure
Quaternary Structure • Interaction between two domains • Large cytoplasmic domains • C1a • C2b
Quaternary Structure • Adenylyl cyclase interaction with G protein
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
Overview sAC is the tenth form of AC. It is soluble and only found in sperm
Activation Forskolin - increases affinity - increases stability - enhances activity Forskolin
Catalysis Mechanism ATP → cAMP +PPi → + ATP cAMP pyrophosphate
Role of Cyclic AMP Step 1: activates protein kinases Step 2: protein kinases phosphorylate substrate proteins Step 3: activated substrate proteins regulate hormone production
ADENYLYL CYCLASE RECEPTOR GDP GTP
Regulation by Receptors Alpha-adrenergic receptors: - Stimulate Gi Proteins Beta-adrenergic receptors: - Stimulate Gs Proteins G Protein Coupled Receptor
CALCIUM/CALMODULIN CA2+ ions CALMODULIN
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.