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Title: Charged repetitive protein sequences in the modification of the host red blood cell by the malaria parasite
Author: Davies, H. M.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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During the symptomatic asexual stage of its life cycle, the malaria parasite P. falciparum exports proteins into the host erythrocyte to modulate its properties. Many exported proteins are targeted to the cell periphery where they affect cell deformability, adhesion, and nutrient import. These changes are implicated in causing severe manifestations of the disease. We have identified novel protein modules which are capable of targeting to the periphery of the red blood cell and which may be involved in modulating these important changes. These were all composed of lysine-rich repetitive sequences, which were shown to be functional in ten proteins altogether, including one protein from the zoonotic P. knowlesi species. Some were found in proteins known to modulate erythrocyte rigidity and cytoadhesion while others were previously uncharacterised. One protein, the glutamic acid-rich protein (GARP), contains three lysine-rich repeating sequences with a peripheral-targeting function. Such repetitive sequences are highly enriched in P. falciparum yet very few have been shown to be functional. Targeting efficiency was shown to be directly affected by the number of repeats present; suggesting that expansion of short non-functional lysine-rich sequences can lead to the de novo formation of localisation sequences. This is observed by comparing the protein sequences of closely related Plasmodium species where repeat expansion has led to functional targeting sequences in some but not others. Additionally, we show that the length of many functional repetitive sequences is highly variable between parasite isolates. Repeat expansion and contraction may allow the parasite to rapidly adapt to selective pressure. Another domain was identified in proteins involved in modulating cytoadhesion and rigidity of host cells in P. falciparum and is conserved across primateinfecting Plasmodium species. Identifying the roles of these novel modules will expand our understanding of parasite-induced erythrocyte modifications and the underlying mechanisms responsible for severe malaria.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available