For the majority of their lifecycle malaria parasites live and replicate within the human red blood cells, where they cause all of the pathological symptoms associated with malaria disease. Invasion of the human red blood cell is essential to their development. This active process is driven entirely by the parasite using a unique actin-myosin motor (right). The motor is housed in the parasite pellicle and linked extra-cellularly to the host cell via secreted adhesins on the parasite surface. The power for motility comes from the force of myosin treading along actin filaments, driving the associated complex rearwards, propelling the parasite into the cell. According to this model, actin filaments function as a ‘molecular clutch’ engaging the motor for active invasion.

Actin is a critical protein for all eukaryotic cells. It has diverse functions from structural roles in the cytoskeleton, to dynamic roles in cell movement and muscle contraction. It exists in two forms: monomeric (G)-actin or filamentous (F)-actin. Uniquely it is able to spontaneously polymerise into filaments. The subunits are not, however, added evenly to both ends, but instead add preferentially to one end, the ‘barbed’ end, whilst being lost from the other, ‘pointed’, end. This biased growth ensures that filament elongation is polarized and gives actin its dynamic properties. However, spontaneous filament growth must be controlled, and cells invest heavily in factors (or regulators) that control actin’s state. The key role actin plays in malaria parasite invasion is demonstrated by drugs that disrupt its ability to polymerise: Drugs that prevent polymerization, block further filament growth, or stabilize F-actin (preventing turnover) all prevent parasite invasion. This demonstrates that malaria parasites require dynamic actin for successful host cell invasion. The tight control of this process in the parasite highlights the importance of actin regulators and earmarks their potential as possible drug targets.

Several studies (including one by our group) have attempted to define the repertoire of actin regulating proteins present in the malaria parasites. Strikingly, most regulators are missing. This includes the ARP2/3 complex an otherwise universal protein complex that determines when and where actin filaments form in cells; a so-called nucleator. In the absence of ARP2/3, the most likely nucleating factor in malaria would be a member of an alternative nucleator family, called the formin proteins. Following this prediction, in work we recently published (see below) malaria parasites have two formin-like proteins with one, PfFormin1, being a potent actin nucleator involved in malaria parasite invasion.

Some useful links

Pubmed
PlasmoDB
Myhits clustalw and multiple seq align hub
OrthoMCL
Pfam protein motifs
NEB Double digests

Some of our collaborations past and present include:

The Cowman Lab at WEHI
The lab of Buzz Baum at UCL, London
The lab of Tom Pollard at Yale University, USA

And we are always interested in new joint projects...

1. Baum J, Tonkin CJ, Paul AS, Rug M, Smith BJ, Gould SB, Richard D, Pollard TD, Cowman AF.

A malaria parasite formin regulates actin polymerization and localizes to the parasite-erythrocyte moving junction during invasion.

Cell Host Microbe . 2008 Mar 13;3(3):188-98

PMID: 18329618 [PubMed - indexed for MEDLINE]

2. Baum J, Papenfuss AT, Baum B, Speed TP, Cowman AF.

Regulation of apicomplexan actin-based motility.

Nat Rev Microbiol . 2006 Aug;4(8):621-8

PMID: 16845432 [PubMed - indexed for MEDLINE]

3. Baum J, Maier AG, Good RT, Simpson KM, Cowman AF.

Invasion by P. falciparum merozoites suggests a hierarchy of molecular interactions.

PLoS Pathog . 2005 Dec;1(4):e37

PMID: 16362075 [PubMed - indexed for MEDLINE]

4. Baum J, Richard D, Healer J, Rug M, Krnajski Z, Gilberger TW, Green JL, Holder AA, Cowman AF.

A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites.

J Biol Chem . 2006 Feb 24;281(8):5197-208

PMID: 16321976 [PubMed - indexed for MEDLINE]

5. Marti M, Baum J, Rug M, Tilley L, Cowman AF.

Signal-mediated export of proteins from the malaria parasite to the host erythrocyte.

J Cell Biol . 2005 Nov 21;171(4):587-92

PMID: 16301328 [PubMed - indexed for MEDLINE]

6. Simpson KM, Baum J, Good RT, Winzeler EA, Cowman AF, Speed TP.

A comparison of match-only algorithms for the analysis of Plasmodium falciparum oligonucleotide arrays.

Int J Parasitol . 2005 Apr 30;35(5):523-31

PMID: 15826644 [PubMed - indexed for MEDLINE]

Research Assistant:	Fiona Angrisano, BBiolSc(Hons) LaT
Undergraduate Student:	David Riglar, BSc Melb