The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin.
Malaria is caused by a protozoan parasite that replicates within an intraerythrocytic parasitophorous vacuole. Release (egress) of malaria merozoites from the host erythrocyte is a highly regulated and calcium-dependent event that is critical for disease progression. Minutes before egress, an essential parasite serine protease called SUB1 is discharged into the parasitophorous vacuole, where it proteolytically processes a subset of parasite proteins that play indispensable roles in egress and invasion. Here we report the first crystallographic structure of Plasmodium falciparum SUB1 at 2.25 Å, in complex with its cognate prodomain. The structure highlights the basis of the calcium dependence of SUB1, as well as its unusual requirement for interactions with substrate residues on both prime and non-prime sides of the scissile bond. Importantly, the structure also reveals the presence of a solvent-exposed redox-sensitive disulphide bridge, unique among the subtilisin family, that likely acts as a regulator of protease activity in the parasite.
Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Chrislaine
C
Withers-Martinez
Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Malcolm
M
Strath
Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Fiona
F
Hackett
Division of Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Lesley F
LF
Haire
Division of Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Steven A
SA
Howell
Division of Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Philip A
PA
Walker
Evangelos
E
Christodoulou
Division of Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Christodoulou
C
Evangelos
Division of Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Guy G
GG
Dodson
Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Michael J
MJ
Blackman
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D020860:Subtilisin / Q000378:metabolism*
D015800:Protozoan Proteins; D020860:Subtilisin; D002118:Calcium