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Structure and function of adenylyl cyclases, key
enzymes in cellular signaling
1,2,3 2,3 1,2,3
Basavraj Khannpnavar , Ved Mehta , Chao Qi and Volodymyr
Korkhov1,2
The adenylyl cyclases (ACs) catalyze the production of the prokaryotes, the mammalian genomes encode only the
ubiquitous second messenger, cAMP, which in turns acts on a class III ACs. Despite the profound differences in the
number of effectors and thus regulates a plethora of cellular structures and domain organization, the six AC classes are
functions. As the key enzymes in the highly evolutionarily functionally very similar, catalyzing the conversion of a
conserved cAMP pathway, the ACs control the physiology of molecule of ATP into cAMP (Figure 1a).
the cells, tissues, organs and organisms in health and disease.
A comprehensive understanding of the specific role of the ACs
Bacterial cAMP systems
in these processes of life requires a deep mechanistic
In bacteria, one of the most extensively studied roles of
understanding of structure and mechanisms of action of these
cAMP is in regulation of the Escherichia coli glucose
enzymes. Here we highlight the exciting recent reports on the
metabolism via the cAMP receptor protein CRP (or
biochemistry and structure and higher order organization of the
catabolite activator protein, CAP) [1]. In addition to its
ACs and their signaling complexes. These studies have
role in regulation of glucose metabolism, CRP can exert
provided the glimpses into the principles of the AC-mediated
profound influence on global gene expression in E. coli via
homeostatic control of cellular physiology.
its influence on more than 380 promoters and 70 transcrip-
Addresses tion factors [2], contributing to the multiple roles of
1
Institute of Biochemistry, ETH Zurich, Switzerland cAMP in processes ranging from carbon metabolism to
2
Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen regulation of virulence phenotypes in pathogenic bacteria
5232, Switzerland
[3–5]. The bacterial cAMP systems also play key roles in
regulation of the cellular homeostasis, phototaxis, protein
Corresponding author: Korkhov, Volodymyr ([email protected])
3 secretion and virulence [6]. For example, in Pseudomonas
Contributed equally.
aeruginosa, cAMP pool generated by adenylyl cyclases
Current Opinion in Structural Biology 2020, 63:34–41 CyaA and CyaB regulates the expression of the type-III
secretion system (T3SS) and other important virulence
This review comes from a themed issue on Membranes
determinants via the cAMP-binding protein Vfr [7].
Edited by Beili Wu and Fei Sun
Many of the bacterial species have evolved the ACs (or
more broadly, nucleotidyl cyclases, NCs) as virulence
https://doi.org/10.1016/j.sbi.2020.03.003 effectors or toxins [8]. These toxins are secreted by the
pathogenic bacteria inside the host cell, hijacking the host’s
0959-440X/ã 2020 The Author(s). Published by Elsevier Ltd. This is an
open access article under the CC BY-NC-ND license (http://creative- cAMP system and aiding the pathogenic bacteria in invad-
commons.org/licenses/by-nc-nd/4.0/). ing the host immune system. The anthrax edema factor
(EF) from Bacillus anthracis is a prototypical and a very
extensively studied AC toxin (REF). Other well-studied
Introduction AC toxins include the Hemolysin-AC CyaA from Bordetella
0 0
pertussis, ExoY from P. aeruginosa, and MARTX ExoY-like
Adenosine 3 ,5 -monophosphate (cAMP) is a ubiquitous
edema factor from Vibrio species [9–12]. These nucleotidyl
signaling molecule across all the domains of life. The
cyclases toxins are active inside the host organisms and
cAMP signaling pathway is a highly conserved regulatory
depend on the host-specific binding partners such as cal-
mechanism that plays a pivotal role in a wide range of
modulin or actin for maximal catalytic activity (REF). The
fundamental cellular process. Adenylyl cyclases (ACs) are
cAMP pool generated by these ACs suppresses the host
the enzymes that generate cAMP, and thus the key
immune system, triggers the reorganization of the actin
components of the cAMP signaling and regulation path-
cytoskeleton causing bleb-niche formation, inter-endothe-
ways. In this review we provide a brief general overview
lial cell gap formation and increased vascular permeability.
of the field, focusing on the recent breakthroughs in our
This ultimately leads to tissue edema and injury, prevent-
understanding of the structure and function of the ACs as
ing the wound healing [8,13].
the key enzymes in cellular signaling.
The ACs in all kingdoms of life include six distinct classes The most abundant class of the ACs, the class III
(class I–VI). Although the six classes are present in enzymes are often coupled to domains that can be used
Current Opinion in Structural Biology 2020, 63:34–41 www.sciencedirect.com
Structure and function of adenylyl cyclases Khannpnavar et al. 35
Figure 1
(a)
Class II CyaA: 1XFV
(b)
Class III AC10: 4CM0
(c)
Class IV YpAC-IV: 3N0Y
Current Opinion in Structural Biology
Representative structures of ACs.
(a) A crystal structure of a class II AC anthrax edema factor showing the key residues involved in binding and catalysis of ATP into cAMP. (b)
Active site architecture of human soluble ACs (AC10) in the presence of an ATP analogue and divalent metal ions. (c) X-ray structure of a class IV
AC from Yersinia pestis, bound to an ATP analogue. Despite the significant differences in structural folds, these ACs are able to maintain similar
active site configurations involving acidic residues for coordination of divalent metal ions and basic residues for stabilization of negatively charged
ATP in the catalytic pocket.
to sense and respond to a variety of stimuli. Because of metabolites, and so on [18]. Some of these proteins have
this feature, the class III ACs can directly receive, amplify been assigned a role in pathogenicity of the mycobacte-
and transmit the information [14]. For example, the rium. This is the case, for example, for Rv0386, which has
adenylate cyclase CyaB responsible for major cAMP pool been shown to be critical for macrophage infection [19].
in P. aeruginosa, is a class III AC coupled to a membrane-
anchored MASE2 sensor domain, which enables the Mammalian ACs
direct regulation of the expression of T3SS and other All mammalian ACs are class III enzymes, with nine
virulence determinants by the environmental stimuli membrane-integral isoforms participating in the GPCR