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J Biol Chem, Vol. 274, Issue 12, 7599-7602, March 19, 1999
From the Laboratory of Molecular Biology, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892-0580
The discovery of 3',5'-cyclic adenosine
monophosphate (cAMP) in the late 1950s by Sutherland and co-workers was
the pivotal event that led to our current paradigm of hormone signaling
through second messengers. Despite the subsequent discovery of many
other second messengers, cAMP has never left center stage. The adenylyl cyclases are the family of enzymes that synthesize cAMP (1-5).
Breakthroughs in determining the first structures of the mammalian
adenylyl cyclase catalytic core (6, 7) provide a new context for
understanding the action of many regulators, both physiological and
pharmacological: free metal ions, P-site inhibitors, forskolin,
G-proteins, Ca2+/calmodulin, and protein phosphorylation.
Understanding the catalytic mechanism of an enzyme is a prerequisite to
understanding its regulation. Here I will describe the essentials of
catalysis and then consider how these elements are controlled by each
of the major regulators.
The nine cloned isoforms of mammalian adenylyl cyclase share a
primary structure consisting of two transmembrane regions, M1 and M2, and two cytoplasmic regions,
C1 and C2 (8) (Fig. 1). The transmembrane regions each
contain six predicted membrane-spanning helices. The function of
M1 and M2, aside from membrane localization, is
unknown despite their topological analogy to transporters. The
C1 and C2 regions are subdivided into
C1a and C1b; and C2a and
C2b. The C1a and C2a are well
conserved, homologous to each other, and contain all of the catalytic
apparatus (9). C1a and C2a domains
heterodimerize with each other in solution (10, 11). These domains can
also form homodimers. Domains derived from different isoforms can form
chimeric heterodimers. The C1b region is large (~15 kDa),
variable, and contains several regulatory sites. The C2b is
vanishingly short in some isoforms and lacks identified functions;
hence C2 and C2a are sometimes referred to
interchangeably.
The structure of the type II adenylyl cyclase C2 region
revealed a homodimer with two C2 monomers in a wreath-like
arrangement (6). A deep ventral groove runs between the two in the
center of the wreath. Two forskolin molecules bind to this groove in the homodimer. The monomer is built around a large The type V C1a region and type II C2 region
arrange themselves in a heterodimeric wreath that is nearly identical
in overall structure to the C2 homodimer, with some
critical differences in detail (7). The active site is at one end of
the ventral groove. The single forskolin binding site, as anticipated
by equilibrium binding (14), is at the other. The active site is formed
at the interface by residues contributed by both C1a and
C2. Because the active site is shared between the two
domains, association of two catalytic domains in the proper orientation
is an absolute prerequisite of catalytic activity. The activity of
mammalian adenylyl cyclases depends on the heterologous association of
C1a and C2. This is not the case for many other
related cyclases (15, 16). Mammalian membrane guanylyl cyclases and
many microbial homologues of mammalian adenylyl cyclases are active as
homodimers. The mammalian C2 homodimer has measurable
activity (9, 17, 18), although reduced by many orders of magnitude
because of the loss of two catalytic Asp residues relative to the heterodimer.
The ATP binding site has been revealed by the structure of the
P-site inhibitor complex (7), molecular modeling (15), and mutagenic
analysis (15, 19-22).
Lys-9231 and Asp-1000 from
C2 interact directly with the N-1 and N-6 of the adenine
ring. Gln-417 of C1 plays a supporting role by orienting the Lys. Mutation of these three residues destroys the ATP
versus GTP nucleotide specificity of adenylyl cyclase,
although it does not convert it into a guanylyl cyclase (22). This is
because of a main chain carbonyl that hydrogen bonds to the adenine N-6 and disfavors guanine. Guanylyl cyclases can be converted completely into adenylyl cyclases by mutating their guanine binding Glu and Cys to
their adenylyl cyclase counterparts, Lys and Asp (21, 22).
The ATP binding site is rounded out by hydrophobic residues that pack
against the purine ring and by charged interactions with phosphate
groups. Hydrophobic contacts are contributed mainly by C2.
Charged interactions are formed by Arg (C1) and Lys
(C2). The Lys is part of a flexible lid over the active
site that is capable of undergoing an order-disorder transition (6,
7).
The Mg2+ binding site consists of two mutationally
sensitive Asp residues (15, 19). The P-site inhibitor complex shows a single Mg2+ ion interacting with both phosphate moieties of
pyrophosphate (7). There is abundant kinetic evidence for a two-ion
mechanism (23, 24). One ion acts kinetically as free Mg2+
whereas the other binds as a complex with ATP. An analogous situation holds for the DNA polymerase family. The polymerases carry out the
intermolecular attack of a primer 3'-hydroxyl on the Two Mg2+ ions bind to DNA
polymerase-primer-template-nucleotide complexes (25-28), providing a
model for the coordination of two ions in the adenylyl cyclase active
site. The polymerase "B" metal ion corresponds to the observed ion
in the adenylyl cyclase complex. It binds all three nucleotide
phosphates in a tridentate arrangement (25, 27). These tight
interactions leave little doubt that this is the ion that acts
kinetically as an ATP complex. The polymerase "A" metal ion is less
tightly bound as judged by higher temperature factors and fewer
interactions with protein and nucleotide (25). It interacts with the
3'-hydroxyl of the primer and the nucleotide Cyclic AMP formation requires the deprotonation and activation of
the ATP 3'-hydroxyl for nucleophilic attack; stabilization of the
transition state at the The determinants of both nucleotide binding and catalysis are
shared between C1 and C2. This insight is
central to understanding regulation of adenylyl cyclase catalytic
activity. It means that any factor that alters the relative orientation
of the C1 and C2 domains can alter the
structure of the active site and thereby alter substrate affinity,
catalytic velocity, or both.
The structure of the catalytic core is known in two conformations: that
of the forskolin-bound homodimer (6) and that of the forskolin and
Gs Mammalian adenylyl cyclases are strongly activated by
Mn2+ and inhibited by millimolar concentrations of free
Ca2+. These effects are unlikely to have any physiological
meaning or to reflect distinct binding sites for these ions. Many
otherwise unrelated Mg2+-dependent enzymes can
be activated by replacing Mg2+ with Mn2+,
probably because the latter is nearly the same size but is a stronger
Lewis acid. At high concentrations free Ca2+ binds
competitively to Mg2+ sites on enzymes but fails to replace
it catalytically. A high affinity and possibly physiological inhibition
of type V and VI adenylyl cyclase by free Ca2+ has been
reported (30), and the possibility of a high affinity binding site in
the C1b domain of these isoforms has been raised (31).
P-site inhibitors are a class of nucleoside inhibitors of adenylyl
cyclase so-called because they all contain a purine ring (32). The most
potent lack a 2'-hydroxyl and are polyphosphorylated at the 3'-position
(32-34). P-site inhibition is potentiated when adenylyl cyclase is
activated. P-site inhibition is hypersensitive to certain mutations
that slightly reduce enzyme activity. P-site inhibitors are non- or
uncompetitive with respect to the forward reaction but compete with the
product cyclic AMP in the reverse reaction (35). P-site inhibitors are
effective against engineered ATP-specific guanylyl cyclases that are in
all other ways regulated by different mechanisms than the adenylyl
cyclases (22). P-site inhibitors bind to the active site primarily
through conserved residues. Different adenylyl cyclases do show some
differences in P-site inhibition, and a physiological role for this
type of regulation has been postulated (36).
Forskolin is a hydrophobic activator of all the mammalian adenylyl
cyclases except type IX. It is an extremely powerful activator of some
of the synthetic soluble adenylyl cyclase systems, increasing activity
by up to 103, although other forms of soluble adenylyl
cyclase barely respond. Forskolin binds to the catalytic core at the
opposite end of the same ventral cleft that contains the active site
(7, 15). It activates the enzyme by gluing together the two domains in the core using a combination of hydrophobic and hydrogen bonding interactions that are distributed equally between the two domains (6).
Type IX adenylyl cyclase is non-responsive to forskolin because of
a Ser The forskolin binding pocket is a narrow hydrophobic crevice that
almost completely buries the forskolin molecule once bound. The pocket
residues are absolutely conserved in types I-VIII and differ only
subtly in type IX. The presence of a hydrophobic crevice in a protein
is highly destabilizing in the absence of bound ligand. It seems
improbable that such a destabilizing feature would be so highly
conserved if it had no function. This paradox led us to revive the idea
that there exists an endogenous forskolin-like small molecule activator
of adenylyl cyclase.
All mammalian adenylyl cyclases are potently and physiologically
activated by the GTP-bound G-protein Gi G G-protein interactions with non-catalytic regions of adenylyl cyclase
seem likely. The Ca2+/calmodulin activates type I adenylyl cyclase by
binding to a putative helical region on the C1b (45, 46).
The precise activation mechanism is unknown. If other
Ca2+/calmodulin-activated enzymes are a precedent, it is
likely that Ca2+/calmodulin binding will disrupt an
autoinhibitory interaction between the C1a/C2
catalytic core and sequences within the C1b.
Protein kinase C activates type II adenylyl cyclase by
phosphorylating it on Thr-1057 (47). This site is within a region known
to be required for protein kinase C activation (48). This Thr is at the
edge of the "lid," a flexible region that is disordered in the
homodimer structure but folds over the top of the active site in the
heterodimer-P-site complex. Phosphorylation might enhance the ability
of the lid to adopt the correct conformation. CaM kinase II inhibits
type III adenylyl cyclase by phosphorylating it at Ser-1076 (49). This
Ser is at the outer lip of the active site, hence its phosphorylation
could directly interfere with catalysis. Protein kinase A
phosphorylates Ser-674 in the C1b of type VI (50) and
appears to regulate a low affinity secondary binding site for
Gs A great deal of regulatory complexity has been layered onto the
rather simple core structure of adenylyl cyclase. The core consists of
two parts. The all important two metal ions bind to one part,
C1. The nucleotide binding pocket and other catalytic residues are contributed primarily by the other part, C2.
Both parts need to be aligned to carry out catalysis. The most potent activators of the broad range of mammalian adenylyl cyclases, Gs Progress in understanding the structure and function of the
C1a and C2 regions has not been matched by
information on the rest of adenylyl cyclase. Proposed roles for the
transmembrane segments M1 and M2 as a
transporter or ion channel (8), membrane potential sensor (52, 53), or
Ca2+ channel interaction domain (54) have yet to be proved
or conclusively disproved. Resolution of this mystery would be a major
advance. There are no structural data for C1b,
M1, or M2. For now we must live with a
Who Framed Roger Rabbit picture in which we see the catalytic core in vivid three-dimensional "live action" whereas the
remainder is just a cartoon.
What has the recent burst of progress in the structure and biochemistry
of adenylyl cyclase contributed to the physiology of cAMP signaling?
The possibility has been raised that there are endogenous
forskolin-like or P-site inhibitor small molecule regulators. The
locations of most key regulatory sites are now known. In many cases we
can selectively alter the specificity of these sites, eliminate them,
or even create them at will by site-directed mutagenesis. Transfection
experiments with engineered cyclase isoforms should provide powerful
new tools to determine in vivo how a particular regulator
controls a particular adenylyl cyclase isoform in the context of many
simultaneously active pathways.
*
This minireview will be reprinted
in the 1999 Minireview Compendium, which
will be available in December, 1999.
1
Unless the isoform is explicitly stated,
residue numbering is for type I.
The abbreviations used are:
Gs
MINIREVIEW
Structure, Mechanism, and Regulation of Mammalian Adenylyl
Cyclase*
INTRODUCTION
TOP
INTRODUCTION
REFERENCES
Structure of Adenylyl Cyclase
View larger version (44K):
[in a new window]
Fig. 1.
Structure of adenylyl cyclase. Numbering
is for type I. The crystal structure is shown for the type V
C1 (green)/type II C2
(red) heterodimer bound to forskolin, adenosine
2'-deoxy-3'-monophosphate, pyrophosphate, and one Mg2+
(Gs 
is omitted). Membrane (cream) and
C1b (magenta) regions are drawn. Binding sites
for Gs, Gi (types V and VI), and G
(type II) are black, blue, and yellow,
respectively. The Ca2+/calmodulin binding helix shown is
for type I, and the protein kinase C phosphorylation site shown is for
type II. Atom colors are: carbon, light gray; nitrogen,
blue; oxygen, red; phosphorus, green;
and magnesium, purple. The orientation of the catalytic core
relative to the membrane is arbitrary in this view.
sheet that folds
back onto itself on the "inside" facing the dimer interface. The
"outside" is -helical. A ~80-amino acid substructure within the monomer is similar to the palm domains of the DNA polymerase I and
reverse transcriptase families (12, 13).
Nucleotide Binding Site and Specificity
Mg2+ Binding Site
-phosphate of a
deoxynucleotide rather than the intramolecular attack of a nucleotide
3'-hydroxyl on its own -phosphate.
-phosphate. Both metal
ions are coordinated by both Asps. This coordination geometry fits the
adenylyl cyclase structure consistent with known stereochemistry
(29).
Mechanism of Cyclic AMP Formation
-phosphate; and stabilization of increased
negative charge on the leaving group, pyrophosphate. Metal ion A
activates the 3'-hydroxyl, and both metal ions share in transition
state stabilization. Asn-1007, Arg-1011, and Lys-1047 approach the
phosphate moieties (Fig. 2). Their
modeled interactions with the non-bridging -phosphate oxygens have
poor geometry. It seems likely that at least one of these residues
stabilizes the leaving group. Their precise positions in the ATP
complex and, therefore, their precise roles in catalysis have yet to be determined. The fate of the proton on the 3'-hydroxyl is unknown. It
has been suggested that Asp-354 in adenylyl cyclase or its counterpart
in DNA polymerase could act as a general base in these reactions (15,
26). Substrate-assisted catalysis is the other leading possibility
suggested for base catalysis (7, 20).
View larger version (15K):
[in a new window]
Fig. 2.
Model for the mechanism of adenylyl
cyclase. Metal coordination by phosphates and Asp is derived from
the T7 DNA polymerase structure (25), and the mechanism is adapted from
that of Steitz (28). C1 residues are green, and
C2 residues are red. Numbering is for type I. Interactions regulated by conformational changes are marked. Asp-310
moves about 1 Å between the two conformations, and Asp-354 and Gln-417
move about 2 Å. A hypothetical hydrogen bond between the putative base
Asp-354 and the ATP 3'-hydroxyl is shown. Arg-1011 probably interacts
with the - bridging oxygen of ATP, but its other interactions are
less certain.
A Conformational Change That Controls Domain Orientation and
Active Site Structure
2-bound
heterodimer (7). The two structures differ by a 7o rotation
of the heterodimer C1 domain relative to the correspondent C2 in the homodimer. The domain rotation brings key
catalytic elements from the two domains about 2 Å closer to each
other. The structural differences between the two might be caused by differences in interface residues in the two different dimers, by
occupancy of one versus two forskolin molecules, or, most
probably, by the binding of Gs. Despite some
uncertainties about which of these factors are driving the observed
structural change, there is no doubt that the two boughs of the
adenylyl cyclase wreath are capable of moving into more or less active conformations.
Regulation by Free Metal Ions
Regulation by P-site Inhibitors
Regulation by Forskolin
Ala and a Leu Tyr change in the binding pocket. When
these changes are reversed by site-directed mutagenesis, the resulting
type IX mutant can be activated by forskolin as well as other adenylyl
cyclases (37).
Regulation by G-protein Subunits
-subunit Gs.
This activation is synergistic, not competitive, with respect to
forskolin. GTP-Gs binds to a crevice on the outside of
the wreath formed by 2' and 3' of C2 and by the
N-terminal portion of C1 (7, 38, 39). GTP-Gs
is capable of gluing together C1 and C2 as does
forskolin, but mutational analysis suggests this cannot be its only
function. If the C1 contact is abolished, activation can be
partially rescued when forskolin is used to dimerize C1 and
C2. Therefore there must be a non-glue role for
GTP-Gs (38). This role is probably to induce a
conformational change that allosterically stimulates catalysis. The
7o rotation of C1, which moves the catalytic
residues into their proper positions, is probably the result of a
torque applied by Gs as it "pushes" the
C1 away from its binding site (7).
selectively inhibits adenylyl cyclase types V and VI.
Symmetry and sequence homology arguments led to the suggestion that Gi binds to the adenylyl cyclase catalytic core on a
groove pseudosymmetrically related to the Gs binding
groove (7, 38). Mutational analysis confirmed that the groove formed by
2 and 3 of C1 is the primary site for binding of
Gi to type V (40). The inhibitory mechanism postulates a
rotation of the C1 in the opposite sense as that induced by Gs.
subunits conditionally regulate several adenylyl cyclases. Type
II adenylyl cyclase is activated by G when Gs is
bound. At least part of the G binding site of type II has been
located using peptide competition studies (41). The site spans a
flexible loop between 3' and 3' and the first two-thirds of 3'
(6). The G site is adjacent to, but does not overlap, the
Gs site, consistent with conditional activation.
4-6 region of Gs was predicted
to interact with adenylyl cyclase based on mutagenic analysis (42, 43),
but no such contact with the catalytic domain was seen in the crystal
structure. G regulation of the soluble adenylyl cyclase model has
not been established, even though the known binding site is located
within the type II C2 domain. C1b (44), M1, or M2 might be involved in either of these processes.
Regulation by Ca2+/Calmodulin
Regulation by Protein Phosphorylation
. CaM kinase IV phosphorylates type I adenylyl cyclase
in its C1b domain and disables Ca2+/calmodulin
activation by interfering with the calmodulin binding site (51).
Conclusions and Perspectives
and forskolin, bind to the domain interface and
thereby control domain orientation in a powerful and direct manner. The
small molecule forskolin binds on the inside, whereas the large protein activator binds to the outside of the wreath. More specialized regulatory sites have been added to the surface of the catalytic domain
(G, protein kinase C) or appended to it
(Ca2+/calmodulin, protein kinase A). The structural work
reinforces the concept of mammalian adenylyl cyclases as sophisticated
coincidence detectors and provides a new framework for a precise
understanding of regulation.
FOOTNOTES
To whom correspondence should be addressed. Tel.: 301-402-4703;
Fax: 301-496-0201; E-mail: jh8e{at}nih.gov.
ABBREVIATIONS
, stimulatory G-protein subunit;
Gi, inhibitory
G-protein subunit;
G, G-protein subunit;
CaM kinase, Ca2+/calmodulin-dependent protein kinase.
REFERENCES
TOP
INTRODUCTION
REFERENCES
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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A. P. LeBeau, F. Van Goor, S. S. Stojilkovic, and A. Sherman Modeling of Membrane Excitability in Gonadotropin-Releasing Hormone-Secreting Hypothalamic Neurons Regulated by Ca2+-Mobilizing and Adenylyl Cyclase-Coupled Receptors J. Neurosci., December 15, 2000; 20(24): 9290 - 9297. [Abstract] [Full Text] [PDF]
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 N. Defer, M. Best-Belpomme, and J. Hanoune Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase Am J Physiol Renal Physiol, September 1, 2000; 279(3): F400 - F416. [Abstract] [Full Text] [PDF]
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 J. A. G. Ochoa de Alda, G. Ajlani, and J. Houmard Synechocystis Strain PCC 6803 cya2, a Prokaryotic Gene That Encodes a Guanylyl Cyclase J. Bacteriol., July 1, 2000; 182(13): 3839 - 3842. [Abstract] [Full Text]
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N. M. Nathanson A multiplicity of muscarinic mechanisms: Enough signaling pathways to take your breath away PNAS, June 6, 2000; 97(12): 6245 - 6247. [Full Text] [PDF]
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 P. Rossler, C. Kroner, J. Krieger, D. Lobel, H. Breer, and I. Boekhoff Cyclic Adenosine Monophosphate Signaling in the Rat Vomeronasal Organ: Role of an Adenylyl Cyclase Type VI Chem Senses, June 1, 2000; 25(3): 313 - 322. [Abstract] [Full Text] [PDF]
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R. Schaloske, C. Schlatterer, and D. Malchow A Xestospongin C-sensitive Ca2+ Store Is Required for cAMP-induced Ca2+ Influx and cAMP Oscillations in Dictyostelium J. Biol. Chem., March 17, 2000; 275(12): 8404 - 8408. [Abstract] [Full Text] [PDF]
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 S. McKinley and J. Hazel Does membrane fluidity contribute to thermal compensation of beta-adrenergic signal transduction in isolated trout hepatocytes? J. Exp. Biol., January 2, 2000; 203(3): 631 - 640. [Abstract] [PDF]
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 J. L. Zeiders, F. J. Seidler, and T. A. Slotkin Agonist-Induced Sensitization of beta -Adrenoceptor Signaling in Neonatal Rat Heart: Expression and Catalytic Activity of Adenylyl Cyclase J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 503 - 510. [Abstract] [Full Text]
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E. K. Jackson, W. A. Herzer, S. J. Vyas, and C. K. Kost Jr Angiotensin II-Induced Renal Vasoconstriction in Genetic Hypertension J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 329 - 334. [Abstract] [Full Text]
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O. Kudlacek, T. Mitterauer, C. Nanoff, M. Hohenegger, W.-J. Tang, M. Freissmuth, and C. Kleuss Inhibition of Adenylyl and Guanylyl Cyclase Isoforms by the Antiviral Drug Foscarnet J. Biol. Chem., January 26, 2001; 276(5): 3010 - 3016. [Abstract] [Full Text] [PDF]
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V. Ramamurthy, C. Tucker, S. E. Wilkie, V. Daggett, D. M. Hunt, and J. B. Hurley Interactions within the Coiled-coil Domain of RetGC-1 Guanylyl Cyclase Are Optimized for Regulation Rather than for High Affinity J. Biol. Chem., July 6, 2001; 276(28): 26218 - 26229. [Abstract] [Full Text] [PDF]
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W. E. McIntire, G. MacCleery, and J. C. Garrison The G Protein beta Subunit Is a Determinant in the Coupling of Gs to the beta 1-Adrenergic and A2a Adenosine Receptors J. Biol. Chem., May 4, 2001; 276(19): 15801 - 15809. [Abstract] [Full Text] [PDF]
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