Guanylyl cyclase activity associated with putative bifunctional integral membrane proteins in Plasmodium falciparum

We report here that guanylyl cyclase activity is associated with two large integral membrane proteins (PfGC alpha and PfGC beta) in the human malaria parasite Plasmodium falciparum. Unusually, the proteins appear to be bifunc tional; their amino-terminal regions have strong similarity with P-type ATP ases, and the sequence and structure of the carboxyl-terminal regions confo rm to that of G protein-dependent adenylyl cyclases, with two sets of six t ransmembrane sequences, each followed by a catalytic domain (C1 and C2), Ho wever, amino acids that are enzymatically important and present in the C2 d omain of mammalian adenylyl cyclases are located in the C1 domain of the P. falciparam proteins and vice versa, In addition, certain key residues in t hese domains are more characteristic of guanylyl cyclases, Consistent with this, guanylyl cyclase activity was obtained following expression of the ca talytic domains of PfGC beta in Escherichia coli, In P. falciparum, express ion of both genes was detectable in the sexual but not the asexual blood st ages of the life cycle, and PfGC alpha was localized to the parasite/parasi tophorous vacuole membrane region of gametocytes, The profound structural d ifferences identified between mammalian and parasite guanylyl cyclases sugg est that aspects of this signaling pathway may be mechanistically distinct.