trans

CYCLIC NUCLEOTIDES 263
Plasmodium guanylyl cyclase
Receptor/transporter
function?
ATPase
domain
Cyclase
domain
GTP
cGMP
Regulatory
cofactors?
?
?
FIGURE 11.5 (See also Color Plate 7) Model for the structure of Plasmodium guanylyl cyclase (GC). The amino
acid sequences of the P. falciparum GCs (PfGC and PfGC) suggest that they are bifunctional integral membrane
proteins. The amino terminal regions have similarities to P-type ATPases of other organisms and the topology of
the carboxy terminal regions conforms to that of mammalian G-protein-dependent adenylyl cyclases (Figure
11.4A). The function of the ATPase domain remains to be determined, but the catalytic regions (C1 and C2) exhibit
GC activity. cGMP-dependent protein kinase (PKG) is thought to have a role in signal transduction, although the
mechanisms involved have not been characterized. Similarly, little is known about regulatory cofactors that could
act directly on the GC catalytic regions.
domain may act as a receptor and be functionally,
as well as physically, linked to the GC protein.
Cyclases with the unusual topology of the
Plasmodium GC have also been identified in
the taxonomically related ciliates Paramecium
and Tetrahymena.
In P. falciparum, expression of both GC
mRNAs was detectable in the sexual, but not the
asexual, stages of the life cycle, and PfGC has
been localized to the parasite/parasitophorous
vacuole membrane region. In agreement with
this observation, GC activity is associated predominantly
with the membrane fractions of
mature gametocytes. GC activity is Mg 2 /Mn 2
dependent, but can be inhibited by Ca 2 . From
a functional perspective it is not immediately
obvious why the malaria parasite has two
proteins with the same activity that are both
expressed during the sexual stages of the life
cycle. One possibility is that they are expressed
differentially during this complex life-cycle
phase. Another is that they are co-expressed,
but that they respond to different activators.
Both PfGC and PfGC are encoded by large
single-copy genes that differ in an interesting
way. The PfGCa sequence is uninterrupted by
introns, but PfGCb contains 13, with all but one
being confined to the ATPase domain (Figure
11.6). It can be presumed that the progenitor
PfGC protein arose from the fusion of two
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA