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Title: Characterisation of the human Arl4 and Arl8 families of small GTPases
Author: Hofmann, Irmgard Maria Rita
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Two closely related human Arls, Arl8a and Arl8b, were found to localise to lysosomes in mammalian cells. conventionally, membrane binding of Arf and Arl proteins is mediated by both an N-terminal myristoyl group and an N-terminal amphipathic helix that are inserted into the lipid bilayer upon activation of the GTPase. Arl8 GPTases lack myristolylation sites, and examination of the N-terminus of Arl8b revealed that it contains an acetyl group instead, and this acetylated methionine is necessary for its lysosomal location. Lysosomes of cells overexpressing Arl8b move more frequently, suggesting a role for Arl8a and Arl8b as positive regulators of lysosomal transport. Arl4a, Arl4c and Arl4d are very similar in sequence and were found to act in a pathway upstream of Arf6, Arf6 is a regulator of key processes at the plasma membrane, such as endocytosis, actin dynamics and cell adhesion. One of the major activators of Arf6 is the exchange factor ARNO (‘Arf nucleotide binding site opener’). In order to activate Arf6, ARNO must translocate from the cytoplasm onto the plasma membrane. ARNO was identified as an interaction partner of Arl4 GTPases in a yeast two hybrid screen, and Arl4 GTPases mediate membrane translocation of ARNO. Thus, Arl4 GTPases represent a novel signal transduction pathway upstream of Arf6. This study provides a characterisation of members of the human Arl family and suggests functions for Arl4 and Arl8 GTPases in membrane traffic related processes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available