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Title: Regulation of DHHC5 localisation by palmitoylation of Golga7b has effects on DHHC5 interactions, endocytosis and cell adhesion
Author: Woodley, Keith
ISNI:       0000 0004 7972 0296
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Among post-translational modifications, palmitoylation, also known as S-acylation, is uniquely positioned as the only fully reversible lipid modification and aberrant palmitoylation has been linked to problems with a number of cellular processes. Despite this, little is known about the palmitoyl-acyltransferase enzymes which mediate the attachment of the lipid to proteins. Among these enzymes, DHHC5 is unique as it resident at the plasma membrane and has an extended C-terminal tail that can be modified by palmitoylation, among other PTMs. In this work, it has been shown that DHHC5 needs to palmitoylate a novel substrate and regulator, Golga7b, in order for it to be stabilised at the plasma membrane and that preventing palmitoylation of Golga7b causes DHHC5 to be mis-localised to regions within the cell. However, palmitoylation of Golga7b is not the only palmitoylation event that is important for DHHC5 localisation, as halting palmitoylation of the DHHC5 C-terminal tail prevents endocytosis of DHHC5 and traps the protein at the plasma membrane. By using affinity purification-mass spectrometry, a range of processes that DHHC5 could be involved with and that regulate DHHC5 were revealed. Among these, it was shown that DHHC5 is endocytosed by a mechanism that requires the AP2 complex and depleting this complex or blocking endocytosis another way, causes DHHC5 to be trapped at the plasma membrane. Also revealed by the AP-MS was the high enrichment of adhesion proteins and it was later proven that DHHC5 palmitoylates a pair of desmosomal proteins and has a wider role in cellular adhesion. Together the work presented here uncovers more about the regulation of the location of DHHC5 by a number of factors including palmitoylation of itself and an interacting protein and endocytosis of DHHC5 and goes on to show that DHHC5 has a central role in proper cell adhesion.
Supervisor: Collins, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available