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Elucidating the role of BEACH domain-containing proteins, which are mutated in several diseases, using a simple eukaryotic model organism, Saccharomyces cerevisiae

dc.contributor.advisorSchwappach-Pignataro, Blanche Prof. Dr.
dc.contributor.authorDreyling, Anna Dominika
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.titleElucidating the role of BEACH domain-containing proteins, which are mutated in several diseases, using a simple eukaryotic model organism, Saccharomyces cerevisiaede
dc.contributor.refereeSchwappach-Pignataro, Blanche Prof. Dr.
dc.description.abstractengMutations in BEACH domain-containing proteins (BDCPs) cause various human diseases, such as the Chediak-Higashi syndrome, the generalised autoimmunity syndrome or the gray platelet syndrome. Furthermore, a variety of other diseases, such as autism, systemic lupus erythematosus or glioma, have been associated with this group of proteins, underlining its medical relevance. Consisting of around 300 amino acids, the BEACH domain itself is a highly conserved domain present in eukaryotes. It is typically flanked by other conserved regions, such as the Pleckstrin Homology (PH) domain, the 5xWD40 repeat domain or the domain of unknown function 1088 (DUF 1088). Bph1 (beige protein homolog 1), the only BDCP present in yeast, encompasses all four domains, making Saccharomyces cerevisiae with its genetic tractability an ideal model organism to elucidate the basic function of BDCPs. Although their precise role remains unknown, BDCPs are putatively involved in membrane dynamics, vesicular trafficking or receptor signaling. During this study, the absence of Bph1 was shown to result in the disturbance of vesicular trafficking during the late secretory pathway, while not affecting the early secretory pathway. Additionally, different reporters exposing di-lysine or Arg-based ER retrieval signals were consistent with completely independent functions of Bph1 and COPI, a vesicular carrier involved in the transport of cargo from the Golgi complex to the ER. Using microscopy, Bph1 has been shown to be either located at the vacuole or punctated at the Golgi complex/endosomes. Additionally, Bph1 was confirmed to be required for proliferating in the presence of Calcofluor white or potassium acetate, which serve as indicators of faulty post Golgi trafficking routes. Truncation constructs were designed, consisting of the BEACH domain, the 5xWD40 repeat domain, the PH domain and the DUF 1088. All partial Bph1 domain constructs were expressed to detectable levels, albeit at different intensity levels. Further optimisation of the expression levels will be required to map the necessary and sufficient domain(s) of Bph1, using the constructs in functional complementation
dc.contributor.coRefereeThumm, Michael Prof. Dr.
dc.subject.engBEACH domainde
dc.subject.engfunctional complementationde
dc.subject.engvesicular traffickingde
dc.subject.engsecretory pathwayde
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullMedizin (PPN619874732)de
dc.subject.gokfullBiochemie / Physiologische Chemie / Pathobiochemie - Allgemein- und Gesamtdarstellungen (PPN619875313)de

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