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plasmepsins

NOT Open Access | Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway

May 13, 2020 - 13:54 -- NOT Open Access
Author(s): 
Rathore I, Mishra V, Patel C, Xiao H, Gustchina A, Wlodawer A, Yada RY, Bhaumik P
Reference: 
FEBS J. 2020 May 9

Plasmodium parasites that cause malaria produce plasmepsins (PMs), pepsin‐like aspartic proteases that are important antimalarial drug targets due to their role in host hemoglobin degradation. The enzymes are synthesized as inactive zymogens (pro‐PMs) and the mechanism of their conversion to the active, mature forms has not been clearly elucidated. Our structural investigations of vacuolar pro‐PMs with truncated prosegment (pro‐tPMs) reveal that the formation of the S‐shaped dimer is their innate property. Further structural studies, biochemical analysis, and molecular dynamics simulations indicate that disruption of the Tyr‐Asp loop (121p‐4), coordinated with the movement of the loop L1 (237‐247) and helix H2 (101p‐113p) are responsible for the extension of the pro‐mature region (harboring the cleavage site).

Malaria parasite plasmepsins: More than just plain old degradative pepsins

May 6, 2020 - 15:57 -- Open Access
Author(s): 
Armiyaw S. Nasamu, Alexander J. Polino, Eva S. Istvan and Daniel E. Goldberg
Reference: 
J Biol Chem. 2020 May 4. pii: jbc.REV120.009309

Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium. Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g., plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous.

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