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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 4

Module 2: Figure adenylyl cyclase structure

TM 1-6 TM 7-12
C1 C2 AC 1 - 9

C1 C2 AC 10

Plasma membrane
1 2 3 4 5 6 7 8 9 10 11 12

C1 C2
O O
O P O P O
O O Pyrophosphate
NH 2 NH 2
N N
N N
H H O O O H H
N N
N C O P O P O P O N C
O O O
O O O
O P
ATP OH OH Cyclic AMP OH O O
Domain structure of adenylyl cyclase (AC).
The nine membrane-bound adenylyl cyclases (AC1--AC9) have a similar domain structure. The single polypeptide has a tandem repeat of six
transmembrane domains (TM) with TM1--TM6 in one repeat and TM7--TM12 in the other. Each TM cassette is followed by large cytoplasmic domains
(C1 and C2), which contain the catalytic regions that convert ATP into cyclic AMP. As shown in the lower panel, the C1 and C2 domains come together
to form a heterodimer. The ATP-binding site is located at the interface between these two domains. The soluble AC10 isoform lacks the transmembrane
regions, but it retains the C1 and C2 domains that are responsible for catalysis.

characterized by having two regions where there are six tein kinase A (PKA)]. Of the two types of PKA, protein
transmembrane regions (Module 2: Figure adenylyl cy- kinase A (PKA) I is found mainly free in the cytoplasm
clase structure). The large cytoplasmic domains C1 and and has a high affinity for cyclic AMP, whereas protein
C2, which contain the catalytic region, form a heterodimer kinase A (PKA) II has a much more precise location by be-
and co-operate with each other to convert ATP into cyclic ing coupled to the A-kinase-anchoring proteins (AKAPs).
AMP. The AKAPs are examples of the scaffolding proteins that
function in the spatial organization of signalling pathways
by bringing PKA into contact with its many substrates.
Cyclic AMP signalling effectors
The scaffolding function of the AKAPs is carried out by
Cyclic AMP is a highly versatile intracellular messen-
ger capable of activating a number of different effectors various domains such as the conserved PKA-anchoring
(Module 2: Figure cyclic AMP signalling). An example of domain [yellow region in Module 2: Figure protein kinase
such effectors is the exchange proteins activated by cyc- A (PKA)], which is a hydrophobic surface that binds to
lic AMP (EPACs), which act to stimulate Rap. Another an extended hydrophobic surface on the N-terminal di-
group of effectors are the cyclic nucleotide-gated channels merization region of the R subunits. At the other end of
(CNGCs) (Module 3: Figure Ca 2 + entry mechanisms)that the molecule, there are unique targeting domains (blue)
play a particularly important role in the sensory systems that determine the way AKAPs identify and bind specific
responsible for smell and taste. Most of the actions of cyclic cellular targets in discrete regions of the cell.
AMP are carried out by protein kinase A (PKA).
Protein kinase A (PKA) I
Protein kinase A (PKA) Type I protein kinase A (PKA) associates with the RI iso-
Many of the actions of cyclic AMP are carried out by pro- forms. As for all isoforms, the R subunits form dimers
tein kinase A (PKA), which phosphorylates specific sites through their N-terminal dimerization/docking domains
on downstream effector processes (Module 2: Figure cyc- [yellow bar in Module 2: Figure protein kinase A (PKA)].
lic AMP signalling). PKA is composed of two regulatory In addition to holding two R subunits together, this N-
(R) subunits and two catalytic (C) subunits. The way in terminal region is also responsible for docking to the A-
which cyclic AMP activates PKA is to bind to the R sub- kinase-anchoring proteins (AKAPs), as occurs for PKA
units, which then enables the C subunits to phosphorylate II. However, the RI isoforms have a very low affinity for
a wide range of different substrates [Module 2: Figure pro- the AKAPs and are thus mainly soluble. Cyclic AMP acts

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