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  • Review Article
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Post-translational protein modifications in malaria parasites

Nature Reviews Microbiology volume 13, pages 160–172 (2015)Cite this article

Subjects

Key Points

  • The modification of proteins by addition of various chemical groups is pervasive at all stages of the life cycle of malaria parasites; such modifications can regulate the activity, localization, interactions and other properties of the target proteins.

  • The post-translational modifications (PTMs) that have been most extensively studied in malaria parasites are phosphorylation (notably in the context of signalling pathways), acetylation and methylation (notably in the context of epigenetic control of gene expression), and lipidation (notably in the context of membrane association).

  • The enzymes that mediate PTM of proteins in malaria parasites fulfil many essential functions along the parasites' life cycle and are, in many instances, sufficiently divergent from their mammalian homologues to provide opportunities for selective inhibition by small molecules; therefore, they are attractive potential targets for novel curative and/or transmission-blocking antimalarial drugs.

Abstract

Post-translational modifications play crucial parts in regulating protein function and thereby control several fundamental aspects of eukaryotic biology, including cell signalling, protein trafficking, epigenetic control of gene expression, cell–cell interactions, and cell proliferation and differentiation. In this Review, we discuss protein modifications that have been shown to have a key role in malaria parasite biology and pathogenesis. We focus on phosphorylation, acetylation, methylation and lipidation. We provide an overview of the biological significance of these modifications and discuss prospects and progress in antimalarial drug discovery based on the inhibition of the enzymes that mediate these modifications.

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Figure 1: Plasmodium spp. life cycle.
Figure 2: Modes of phospho-regulation of malaria parasite protein kinases.
Figure 3: Histone H3 post-translational modifications.
Figure 4: Classes and functions of protein lipidation.

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Acknowledgements

The authors thank D. Mitcheson for the original contribution to Figure 1. Research in the laboratories of A.S., J.C.R. and C.D. was supported by the European Union FP7 Network of Excellence EviMalaR. C.D.'s laboratory is supported by Monash University, the Australian National Health and Medical Research Council and the Australian Centre for HIV and Hepatitis Virology Research. J.C.R. is supported by the Wellcome Trust (098051). A.S. is supported by the French Parasitology consortium ParaFrap (ANR-11-LABX0024) and ERC Advanced grant PlasmoEscape (250320). A.B.T. is funded by the Medical Research Council (Programme Leader — Toxicology Unit).

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Authors and Affiliations

  1. Department of Microbiology, Faculty of Biomedical and Psychological Sciences, Monash University, Wellington Road, Clayton, 3800, Victoria, Australia

    Christian Doerig

  2. Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

    Julian C. Rayner

  3. Biology of Host–Parasite Interactions Unit, Institut Pasteur, 25 rue du Dr. Roux, Paris, 75015, France

    Artur Scherf

  4. CNRS URA2581, Institut Pasteur, 25 rue du Dr. Roux, Paris, 75015, France

    Artur Scherf

  5. Medical Research Council Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN, UK

    Andrew B. Tobin

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  1. Christian Doerig
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Correspondence to Christian Doerig.

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Supplementary information

Supplementary information S1 (table)

Histone mark writers in P. falciparum (PDF 197 kb)

Supplementary information S2 (table)

Histone mark readers in P. falciparum (PDF 200 kb)

PowerPoint slides

Glossary

Hypnozoite

The dormant liver-stage form of the parasite that develops when a sporozoite invades a liver cell. Several human (Plasmodium vivax and Plasmodium ovale) and monkey (Plasmodium cynomolgi) malaria parasite species develop dormant liver stages that become activated several weeks, or even years, later, resulting in a blood-stage infection.

Phosphorylation

Covalent attachment of a phosphate group to a molecule. Protein phosphorylation is a particular case, in which the phosphate is transferred from ATP (or, in some cases, GTP) to an amino acid within a polypeptide. Eukaryotic protein kinases target residues with an alcohol group (that is, serine, threonine and tyrosine); other amino acids that do not carry an alcohol group, such as histidine or aspartic acid, can also be phosphorylated, notably (but not exclusively) in prokaryotic systems.

Kinome

The ensemble of all the genes in the genome of an organism that encode protein kinases. In eukaryotes, this typically represents 1–2% of the total number of genes.

Alveolates

A major superphylum of unicellular eukaryotes that comprises several phyla, including the Apicomplexa (to which Plasmodium spp. belong), the Chromerids (the closest free-living and photosynthetic relatives of Apicomplexa), the Ciliates and the Dinoflagellates. Alveolates are named after the so-called cortical alveoli, which are characteristic vesicles that form a layer underneath the plasma membrane called the inner membrane complex, a feature that is shared by all members of the superphylum.

Antigenic variation

A mechanism by which a malaria parasite alters its surface proteins in order to evade a host immune response.

Heterochromatin

Highly compact and therefore transcriptionally inactive regions of the genome. In Plasmodium falciparum, the histone H3 lysine 9 trimethylation (H3K9me3) mark recruits heterochromatin protein 1 (PfHP1) to form facultative heterochromatin. This is key to expression control of clonally variant gene families.

Histone writers

Molecules that attach modifications to histones at a specific modified site.

Histone readers

Molecules that bind to a specific modified site in histones.

Prenylation

Covalent attachment of either a farnesyl moiety (farnesylation) or a geranylgeranyl moiety (geranylation) to cysteine residues.

Myristoylation

Covalent attachment of myrisitic acid (a 14-carbon saturated fatty acid) to the amino-terminal glycine residue of a protein. Myristoylation occurs via an irreversible amide bond.

Palmitoylation

Covalent attachment of a long-chain fatty acid (typically, but not always, palmitic acid, a 16-carbon saturated fatty acid) to cysteine residues via a thioester bond. In the most common form (S-palmitoylation), attachment occurs at an internal cysteine residue, and the thioester bond is reversible. In other eukaryotes, attachment can also occur irreversibly at an amino-terminal cysteine; whether N-palamitoylation occurs in Plasmodium falciparum is not currently known.

Glycosylphosphatidylinositol anchor

(GPI anchor). Glycolipids that are attached to the carboxyl terminus of a protein to mediate surface attachment of the protein. GPI anchors are synthesized from fatty acid and carbohydrate precursors by a multi-step process that occurs in the secretory pathway.

Inner membrane complex

A morphological feature shared by all Alveolates that is composed of flattened vesicles underlying the plasma membrane. It is associated with the cytoskeleton and has roles in structural strengthening, motility and cytokinesis.

Rhoptry

A specialized secretory organelle at the apical end of the motile parasite. Along with other secretory organelles (the micronemes and the dense granules), rhoptries contain proteins involved in host cell invasion and subsequent modification of the host cell.

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Doerig, C., Rayner, J., Scherf, A. et al. Post-translational protein modifications in malaria parasites. Nat Rev Microbiol 13, 160–172 (2015). https://doi.org/10.1038/nrmicro3402

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