Proteolytic activity of Plasmodium falciparum subtilisin-like protease 3 on parasite profilin, a multifunctional protein

Alam, Asrar; Bhatnagar, Raj K.; Relan, Udbhav; Mukherjee, Paushali; Chauhan, Virander S.

doi:10.1016/j.molbiopara.2013.09.006

Cited by 18 publications

(17 citation statements)

References 19 publications

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“…Plasmodium SUBs similarity is restricted to their catalytic domains, which display 430% sequence identity 10 , and all are expressed during the parasite blood stages [8][9][10] . However, although genetic approaches have shown that SUB3 is dispensable for the development of Plasmodium blood stages 11 , its precise biological role remains to be established 12 ; SUB1 and SUB2 are essential enzymes 11,13 . SUB1 executes the specific processing of proteins involved in the egress of Plasmodium merozoites (Mz) from host hepatocytes or erythrocytes 11,14 , as well as Mz protein surface maturation 15 .…”

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confidence: 99%

“…Plasmodium SUB1 properties fulfill these criteria, as SUB1 is indeed highly conserved across Plasmodium species 9,21 , including P. falciparum and P. vivax, and SUB1 inhibitors have been shown to equally impair P. vivax and P. falciparum SUB1 enzymes 21 . In addition, SUB1 plays a dual essential role at both the hepatic and erythrocytic phases of the Plasmodium life cycle 12 .…”

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confidence: 99%

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A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

et al. 2014

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The Plasmodium subtilase SUB1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. Here we report the crystal structure of full-length SUB1 from the human-infecting parasite Plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a Plasmodium-specific prodomain. The latter displays a novel architecture with an amino-terminal insertion that functions as a 'belt', embracing the catalytic domain to further stabilize the quaternary structure of the pre-protease, and undergoes calcium-dependent autoprocessing during subsequent activation. Although dispensable for recombinant enzymatic activity, the SUB1 'belt' could not be deleted in Plasmodium berghei, suggesting an essential role of this domain for parasite development in vivo. The SUB1 structure not only provides a valuable platform to develop new anti-malarial candidates against this promising drug target, but also defines the Plasmodium-specific 'belt' domain as a key calcium-dependent regulator of SUB1 during parasite egress from host cells.

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A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

et al. 2014

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“…berghei SUB2 is also found in ookinetes, where it has been suggested to play a role in modifying the cytoskeletal network of the invaded mosquito midgut cells (28). SUB3 is the least characterized member of the family, and it is thought to function in host immune evasion (29, 30). …”

Section: Discussionmentioning

confidence: 99%

Plasmodium berghei PIMMS2 Promotes Ookinete Invasion of the Anopheles gambiae Mosquito Midgut

et al. 2017

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Mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. Mosquito infection ensues upon oocyst development that follows ookinete invasion and traversal of the mosquito midgut epithelium. Here, we report the characterization of PIMMS2 (Plasmodium invasion of mosquito midgut screen candidate 2), a Plasmodium berghei protein with structural similarities to subtilisin-like proteins. PIMMS2 orthologs are present in the genomes of all plasmodia and are mapped between the subtilisin-encoding genes SUB1 and SUB3. P. berghei PIMMS2 is specifically expressed in zygotes and ookinetes and is localized on the ookinete surface. Loss of PIMMS2 function through gene disruption by homologous recombination leads to normal development of motile ookinetes that exhibit a severely impaired capacity to traverse the mosquito midgut and transform to oocysts. Genetic complementation of the disrupted locus with a mutated PIMMS2 allele reveals that amino acid residues corresponding to the putative subtilisin-like catalytic triad are important but not essential for protein function. Our data demonstrate that PIMMS2 is a novel ookinete-specific protein that promotes parasite traversal of the mosquito midgut epithelium and establishment of mosquito infection.

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“…Of these, PfSUB1 and 2 have been extensively characterized and implicated in egress and invasion during asexual blood stage life cycle of the parasite [26, 27, 36]. PfSUB3 is the least characterized member and preliminary reports have confirmed the in vitro serine protease activity of PfSUB3 and also identified a multifunctional parasite protein, profilin, as its interacting partner [37, 38]. …”

Section: P Falciparum Serine Proteasesmentioning

confidence: 99%

“…PfPRF was found to induce the secretion of proinflammatory cytokines IL-12 and TNF- α from mouse bone marrow-derived dendritic cells. PfSUB3 showed proteolytic activity on PfPRF in in vitro assays and caused cleavage of PfPRF into multiple fragments of smaller sizes, which were hydrolyzed by increasing concentration of PfSUB3 [38]. It is still not clear if this proteolytic activity causes maturation of PfPRF or degradation under physiological conditions.…”

Section: P Falciparum Serine Proteasesmentioning

confidence: 99%

Serine Proteases of Malaria ParasitePlasmodium falciparum: Potential as Antimalarial Drug Targets

Alam

2014

Interdisciplinary Perspectives on Infectious Diseases

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Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets.

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Proteolytic activity of Plasmodium falciparum subtilisin-like protease 3 on parasite profilin, a multifunctional protein

Cited by 18 publications

References 19 publications

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

Plasmodium berghei PIMMS2 Promotes Ookinete Invasion of the Anopheles gambiae Mosquito Midgut

Serine Proteases of Malaria ParasitePlasmodium falciparum: Potential as Antimalarial Drug Targets

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