A Prioritized and Validated Resource of Mitochondrial Proteins in
            <i>Plasmodium</i>
            Identifies Unique Biology

Esveld, Selma L van; Meerstein-Kessel, Lisette; Boshoven, Cas; Baaij, Jochem F; Barylyuk, Konstantin; Coolen, Jordy P. M.; Strien, Joeri van; Duim, Ronald A J; Dutilh, Bas E.; Garza, Daniel; Letterie, Marijn; Proellochs, Nicholas I.; Ridder, Michelle N de; Venkatasubramanian, Prashanna Balaji; Vries, Laura E. de; Waller, Ross F.; Kooij, Taco W. A.; Huynen, Martijn

doi:10.1128/msphere.00614-21

Cited by 19 publications

(19 citation statements)

References 78 publications

(116 reference statements)

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“…These scores are produced computationally by analyzing N-terminal targeting sequences for the features of mitochondrial targeting peptides (MPII), or by combining multiple factors hypothesized to be common to mitochondrial proteins (PMC). We also obtained scores for a mitochondrial “gold positive” protein set compiled by our group and a non-mitochondrial “gold negative” set of previously published non-mitochondrial proteins [20], and constructed violin plots to compare the distributions of scores (Fig 4C). PMC scoring appeared to provide a more nearly complete separation of the positive and negative sets, although the difference between the average scores of the sets was greater with MPII scoring (S4 Table).…”

Section: Resultsmentioning

confidence: 99%

“…analyzed the N-terminal sequences of putative P. falciparum mitochondrial proteins and developed a neural network program to predict mitochondrial targeting of P. falciparum proteins, which predicted between 381 (7%) to 1,177 proteins (22%) to be targeted to the mitochondrion, depending on the stringency of the network [26]. A more recent study analyzed eight proteomic data sets relevant to mitochondrial protein expression and targeting, and employed Bayesian statistics to generate a list of 445 putative mitochondrial proteins in P. falciparum [20]. While useful, these predicted sets of mitochondrial proteins were not experimentally derived and are observed to contain a certain number of misassignments that varies with the particular analysis and its parameters.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

Lamb

Rios

Shukla

et al. 2022

Preprint

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Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 putative mitochondrial proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

Lamb

Rios

Shukla

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Bender et al analyzed the N-terminal sequences of putative P. falciparum mitochondrial proteins and developed a neural network program to predict mitochondrial targeting of P. falciparum proteins, which predicted between 381 (7%) to 1,177 proteins (22%) to be targeted to the mitochondrion, depending on the stringency of the network [26]. A more recent study analyzed eight proteomic data sets relevant to mitochondrial protein expression and targeting, and employed Bayesian statistics to generate a list of 445 putative mitochondrial proteins in P. falciparum [20]. While useful, these predicted sets of mitochondrial proteins were not experimentally derived and are observed to contain a certain number of misassignments that varies with the particular analysis and its parameters.…”

Section: Discussionmentioning

confidence: 99%

“…We hereafter refer to this set of proteins as a list of "putative mitochondrial" proteins. We retrieved the "MitoProtII" (MPII) [19] and "Plasmodium MitoCarta" (PMC) [20] scores for these 122 proteins to ascertain the degree to which the list is enriched in proteins predicted to be mitochondrial. These scores are produced computationally by analyzing N-terminal targeting sequences for the features of mitochondrial targeting peptides (MPII), or by combining multiple factors hypothesized to be common to mitochondrial proteins (PMC).…”

Section: Fig 3 Protein Biotinylation Dynamics After Different Time Pe...mentioning

confidence: 99%

“…These scores are produced computationally by analyzing N-terminal targeting sequences for the features of mitochondrial targeting peptides (MPII), or by combining multiple factors hypothesized to be common to mitochondrial proteins (PMC). We also obtained scores for a mitochondrial "gold positive" protein set compiled by our group and a non-mitochondrial "gold negative" set of previously published non-mitochondrial proteins [20], and constructed violin plots to compare the distributions of scores (Fig 4C). PMC scoring relative intensity of spectral counts for each protein identified by LC-MS/MS.…”

Section: Fig 3 Protein Biotinylation Dynamics After Different Time Pe...mentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

et al. 2022

View full text Add to dashboard Cite

Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 “putative mitochondrial” proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.

show abstract

Comparative spatial proteomics of Plasmodium-infected erythrocytes

Siau,

Ang,

Sheriff

et al. 2023

Cell Reports

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A Prioritized and Validated Resource of Mitochondrial Proteins in Plasmodium Identifies Unique Biology

Abstract: The unique biology and medical relevance of the mitochondrion of the malaria parasite Plasmodium falciparum have made it the subject of many studies. However, we actually do not have a comprehensive assessment of which proteins reside in this organelle.

Cited by 19 publications

References 78 publications

Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum

Comparative spatial proteomics of Plasmodium-infected erythrocytes

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