The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin

Chrislaine Withers-Martinez (), Malcolm Strath, Fiona Hackett, Lesley F. Haire, Steven A. Howell, Philip A. Walker, Evangelos Christodoulou, Guy G. Dodson and Michael J. Blackman ()
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Chrislaine Withers-Martinez: MRC National Institute for Medical Research, Mill Hill
Malcolm Strath: MRC National Institute for Medical Research, Mill Hill
Fiona Hackett: MRC National Institute for Medical Research, Mill Hill
Lesley F. Haire: MRC National Institute for Medical Research, Mill Hill
Steven A. Howell: MRC National Institute for Medical Research, Mill Hill
Philip A. Walker: MRC National Institute for Medical Research, Mill Hill
Evangelos Christodoulou: MRC National Institute for Medical Research, Mill Hill
Guy G. Dodson: MRC National Institute for Medical Research, Mill Hill
Michael J. Blackman: MRC National Institute for Medical Research, Mill Hill

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4726

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