Crystal structure ofPlasmodium falciparumproplasmepsin IV: the plasticity of proplasmepsins

Abstract

Plasmepsin IV from Plasmodium falciparum (PM IV) is a promising target for the development of novel antimalarial drugs. Here, the crystal structure of the truncated zymogen of PM IV (pPM IV), consisting of the mature enzyme plus a prosegment of 47 residues, has been determined at 1.5 Å resolution. pPM IV presents the fold previously described for studied proplasmepsins, displaying closer similarities to proplasmepin IV from P. vivax (pPvPM) than to the other two proplasmepsins from P. falciparum. The study and comparison of the pPM IV structure with the proplasmepsin structures described previously provide information about the similarities and differences in the inactivation-activation mechanisms among the plasmepsin zymogens.

Activation mechanism of plasmepsins, pepsin‐like aspartic proteases from Plasmodium, follows a unique trans‐activation pathway

“…3A), adjacent to the pro-mature region. A similar interface has been reported for pro-tPMIV [18]. Although pro-tPMII, pro-tPMIV, and Pv-pro-tPM have been crystallized in different space groups, analysis of the crystal contacts indicates that these proteins also create S-shaped dimers in their crystals ( Fig.…”

“…Our analysis also reveals that the Tyr‐Asp loop is missing in the C‐subunit of the pro‐tPMII (http://1PFZ) structure; no justification was provided to rationalize such lack of this structural feature in the previous structural report [17]. Moreover, in the present study it was noted that the C‐terminal part (116p‐120p) of the prosegment of pro‐tPMIV is not well defined in a fragmented electron density [18]. It is likely that the C‐terminal part of the prosegment and the pro‐mature region of pro‐tHAP, as well as of other pro‐tPMs, is more flexible compared to the other parts of the structure.…”

“…However, we had not commented on the pro‐mature region of pro‐tHAP, as this region could not be modeled in that structure. Recently, a high‐resolution crystal structure of pro‐tPMIV has been determined [18]. These structures, along with our newly determined two pro‐tHAP structures (http://6KUB and http://6KUC) with well‐defined prosegments, enabled us to undertake a detailed analysis of the conformational flexibility of the pro‐mature regions among pro‐tPMs.…”

“…Recently, we have shown that the truncated prosegment assists in correct folding of pro‐tPMII, with a mechanism similar to that of pepsin [16]. Crystal structures of pro‐tPMs have been determined for P. falciparum PMII (pro‐tPMII) [17,18], HAP (pro‐tHAP) [19], PMIV (pro‐tPMIV) [18], and P. vivax PM ( Pv ‐pro‐tPM) [20]. These structures revealed that the conformation of the prosegment of pro‐tPMs is unique and different from its counterpart in other pepsin‐like aspartic proteases (Fig.…”

Malaria parasite plasmepsins: More than just plain old degradative pepsins

“…If those enzymes are inhibited, plasmepsin autoprocessing takes place, albeit at a slower rate and at a site 1 amino acid upstream from the normal cleavage site. Structures of P. falciparum PM II, PM III, and PM IV proenzymes as well as those of P. vivax PM IV have been solved (63,(95)(96)(97). The proenzyme of each is inactive because the propiece pushes apart the N-and C-terminal lobes of the protease, keeping the catalytic residues too far apart for activity.…”