The 6-Cysteine (6-Cys) domain is found in Plasmodium proteins that are expressed in all stages of the parasite life cycle in both the vertebrate and mosquito hosts. The domain is of roughly 120 amino acids and contains six positionally conserved cysteines. It might occur in 1-14 copies per protein, either as the sole globular domain or in combination wih β-helix-forming hexapeptide repeats as is the case of sequestrin. It is generally found in tandem pairs of A-type and B-type domains. Previously believed to be exclusive to Plasmodium, the 6-Cys domain also exists in proteins found in all members of the aconoidasidan (hematozoan) clade of Apicomplexa, which unites the haemosporidians (Plasmodium) and piroplasms) [1,2,3,4,5].

The 6-cys domain is a β-sandwich formed by two sheets with a mixture of parallel and antiparallel strands (see <PDB:2LOE>). Three disulfide bonds are present in the 6_Cys domain with C1-C2, C3-C6, and C4-C5 connectivity. C1-C2 and C3-C6 pin together the two sheets of the β-sandwich, whereas C4-C5 links an ancyllary loop to the core domain [4,5].

Some Plasmodium proteins known to contain a 6-Cys domain are listed below:

• Pfs48/45, involved in male/female gamete fusion in the mosquito midgut. It is predicted to be glycosylphosphatidylinositol (GPI)-anchored to the gamete surface.
• Pfs230, involved in male/female gamete fusion in the mosquito midgut. It is a soluble protein that associates with the gamete membrane by binding to Pfs48/45.
• Pfs47, involved in male/female gamete fusion in the mosquito midgut. It is found on female gametes.
• P52, expressed in the sporozoite. May be required for invasion of hepatocytes and to promote normal development in the liver.
• P36, expressed in the sporozoite. May be required for invasion of hepatocytes and to promote normal development in the liver.
• Pf41, located on the surface of merozoites and has a signal sequence.
• Pf38, located on the surface of merozoites. It has a signal sequence and is GPI-anchored to the merozoite surface.
• Pf12, located on the surface of merozoites. It has a signal sequence and is GPI-anchored to the merozoite surface.
• Pf92, located on the surface of merozoites. It has a signal sequence and is GPI-anchored to the merozoite surface.

The profile we developed covers the entire 6-Cys domain.