Table 1.

Biological functions and unique structural features of key Plasmodium proteases.

	Plasmodium
Protease family	protease(s)	Localization; function	Key structural features
Serine proteases	SUB 1	Stored in exonemes and released in to PV on rise of intracellular Ca2+; Egress and Invasion	N-terminal insertion in the prodomain forms a unique “belt” domain which also harbors a Ca2+ binding site unique to all Plasmodium orthologs; Plasmodium-specific insertion of ∼25 residues in the catalytic domain accommodating two Ca2+ ions
	SUB 2	Micronemes; invasion	Structure not determined
Aspartic proteases	Plm II	Digestive vacuole; cleaves native Hb	β-hairpin flap covering the binding cavity and flexible proline rich loop provide huge conformational flexibility at the binding cavity
	Plm V	Endoplasmic reticulum; processing of effector proteins for export to host cells	Presence of highly conserved unpaired cysteine, C140 in flap; presence of unique helix-turn-helix motif distinct from other plasmepsins
	Plm IX, X	Rhoptries and exoneme secretory vesicles; invasion and egress	Structures not determined
Cysteine proteases	FP-2, 2′, 3	Digestive vacuole; principally Hb degradation	N-terminal extension (12 aa) of the mature domain critical for folding; unique anti-parallel β-hairpin motif (14 aa) forming hemoglobin binding domain; Cys99-Cys119 disulfide bond is unique to falcipains unlike other papain-family proteases
	DPAPs	Apical secretory organelles; invasion	Structures not determined
	SERA 5, 6	Parasitophorous vacuole; breakdown of RBC cytoskeleton during egress	Structures not determined
Metalloaminopeptidases	M1AAP, M17LAP	Cytoplasm; protein catabolism	Central disk-like cavity formed by active sites in the hexamer; metal-binding sites (Zn2+) critical for activity