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Title: Tail-anchored proteins at peroxisomes : identification of MIRO1 as a novel peroxisomal motility factor
Author: Castro, Ines Gomes Oliveira
ISNI:       0000 0004 5992 4611
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2016
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Peroxisomes are dynamic and multifunctional organelles, which are essential for human health and development. They are remarkably diverse, with functions that vary significantly between cells and organisms, and can dramatically change their size, shape and dynamics in response to cellular cues. In the past few years, several studies have significantly increased our understanding of the basic principles that enable peroxisome biogenesis and degradation, as well as their pivotal role in cellular signalling and homeostasis. However, several of these processes are still poorly understood. In this thesis we initially studied the peroxisome targeting mechanism of a group of C-terminally anchored membrane proteins, known as tail-anchored (TA) proteins. In order to investigate the molecular signals that enable TA protein targeting to cellular organelles, we analysed the physicochemical properties of a cohort of TA proteins both in silico and in vivo, and show that a combination of transmembrane domain (TMD) hydrophobicity and C-terminal tail charge determines organelle-specific targeting. Focusing on peroxisomes, we demonstrate that a balance between TMD hydrophobicity and high positive tail charge directs TA proteins to this organelle, and enables binding to the peroxisomal chaperone PEX19. These results allowed us to create a bioinformatical tool to predict the targeting of uncharacterised TA proteins and further develop our understanding of the molecular mechanisms involved in the targeting of this protein group. From our initial TA protein screen, we identified the TA protein MIRO1 at peroxisomes and looked at its role in the regulation of peroxisome motility. We show that endogenous MIRO1 localises to mitochondria and peroxisomes, and that dual targeting depends on the C-terminal tail. MIRO1 expression significantly increased peroxisome motility in several cell lines, and revealed a role for motility in peroxisome dynamics, by inducing organelle proliferation and elongation. These results reveal a new molecular complex at peroxisomes and provide us with a tool to further dissect the role of motility on peroxisome function.
Supervisor: Schrader, Michael Sponsor: University of Exeter
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: peroxisome ; tail-anchored proteins ; MIRO1 ; targeting ; motility