Transcript Adenylyl Cyclase FUNCTION

Adenylyl Cyclase
Overview/Structure
What does it do?
Overview- General Structure
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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
Primary Structure Topology
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
Adenylyl Cyclase
Function
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
Activation
Activation
Activation
Catalysis Mechanism
ATP → cAMP +PPi
→
ATP
+
cAMP
pyrophosphate
Catalysis Mechanism
Catalysis Mechanism
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
Regulation
ADENYLYL CYCLASE
RECEPTOR
GDP
GTP
Regulation by Receptors
Alpha-adrenergic receptors:
- Stimulate Gi Proteins
Beta-adrenergic receptors:
- Stimulate Gs Proteins
G Protein Coupled Receptor
G PROTEIN REGULATION
(Guanine Nucleotide-Binding Protein)
ADENYLYL CYCLASE BINDING
Ca2+ Regulation Site
CALCIUM/CALMODULIN
CA2+ ions
CALMODULIN
PKC
(Protein Kinase C)
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.