PREDICTED DISULFIDE-BONDED STRUCTURES FOR 3 UNIQUELY RELATED PROTEINSOF PLASMODIUM-FALCIPARUM, PFS230, PFS48 45 AND PF12/

Pfs230 is a surface protein of the gametes of Plasmodium falciparum an d has been demonstrated to be a target of malaria transmission-blockin g antibodies; it is an important candidate antigen for a transmission- blocking vaccine. The target epitopes of transmission-blocking antibod ies against Pfs230 are almost all reduction sensitive suggesting that disulfide bonds are critical for folding the native molecule. Followin g the cloning of the Pfs230 gene attempts are now underway to express subunits of the protein for use in vaccine trials. It will be importan t to understand the disulfide-bond structure of the Pfs230 to achieve this goal. In this paper we present a model for this structure based o n the observation that the Pfs230 molecule contains a series of regula rly repeated cysteine-containing motifs. Four such motifs have been id entified, together with a fifth cysteineless motif, which occur in the same relative order, with regular alternating omission of specific mo tifs, 14 times throughout the length of the protein. Each of the 14 se ts of motifs contains an even number of cysteine residues (2, 4 or 6). We postulate that each set folds into a separate disulfide-bonded dom ain in which corresponding pairs of cysteines form an equivalent disul fide bond in every such domain. The postulated bonding arrangements in the different domains are mutually confirmatory throughout the sequen ce of Pfs230. We have identified two other malaria proteins, Pfs48/45 and Pf12, which share the same arrangements of motifs and conform to t he same disulfide-bond structure proposed for Pfs230; no other protein s in the sequence data base share these characteristics. Although havi ng similarities to the 'cystine knot' described in other proteins, the arrangement proposed here appears to be unique among described struct ures.