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Title: From force generation to host cell attachment : new function of the acto-MyoA motor complex in Toxoplasma gondii tachyzoites
Author: Latorre-Barragan, Fernanda
ISNI:       0000 0004 7223 9010
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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The Apicomplexan parasite Toxoplasma gondii is considered an extremely successful pathogen for its capacity to invade virtually any nucleated cell. Host cell invasion is an active process thought to be driven by the same acto-myosin machinery that drives gliding motility. The current model suggests that at the core of the complex is MyoA, a small unconventional class XIVa myosin, which, together with its molecular partner myosin light chain 1 (MLC1), produces mechanical force on short actin (ACT1) filaments to power gliding and invasion. However, efficient conditional removal of the key components of the acto-MyoA motor complex indicated that although these proteins were important, they were not essential for motility or invasion. Some plausible explanations of this surprising finding were: probable redundancy among motor complex proteins, presence of residual protein in the conditional mutant lines, and/or compensatory mechanisms for driving these essential steps of the T. gondii life cycle. Considering these hypotheses, and given that T. gondii encodes for 11 myosins and 7 myosin light chains, this study focused on different possibilities upon MyoA and MLC1 depletion, Therefore, overlapping subcellular localisations and functions had to be considered. Due to its structural similarity, and that it shares molecular partners with MyoA, myosin C (MyoC) was the first candidate considered to compensate for MyoA function in the myoA KO. In fact, a myoA/B/C KO was unable to grow in in vitro conditions due to a detrimental egress phenotype, although it could still glide and invade. Here, the mlc1 KO, myoB/C/mlc1 KO, and a set of MyoC complementation constructs in the myoA KO were analysed in deep detail to further investigate the redundancy hypothesis. The results obtained do not dismiss functional redundancies between MyoA and MyoC; on the contrary, they show that some mechanisms, such as egress, can be rescued in the myoA KO. However, this redundancy does not explain how mlc1 and myoB/C/mlc1 KO parasites remain motile and invasive in the absence of residual protein in these conditional mutants. These results make it necessary to critically revisit the current motor model and re-evaluate the functions of the proteins involved in it. This thesis presents evidence that the acto-MyoA motor complex is involved in substrate attachment rather than in force generation. Finally, a hypothetical model for gliding motility is proposed aimed at reconciling recent observations. Together, considering different interactors and mechanisms, these results highlight the complexity of T. gondii tachyzoite cellular biology during progression of the lytic cycle.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR Microbiology