Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Francesca Bottanelli, Freie Universität Berlin, Germany
- Second opponent: Professor Terje Johansen, UiT - The Arctic University of Norway,
- Third member and chair of the evaluation committee: Associate professor Nikolina Sekulic, University of Oslo
Chair of the Defence
Associate Professor Helene Knævelsrud, University of Oslo
Principal Supervisor
Professor Anne Simonsen, University of Oslo
Summary
The family of nine human BEACH domain containing proteins (BDCPs) are linked to a myriad of genetic diseases and health complications. In this thesis, Anette Kathinka Dahl and co-workers provide new knowledge about the localization, structure and function of seven BDCP family members, with a focus on the typical members.
Their data show that the BDCPs localize to distinct endomembrane compartments of the secretory and endocytic pathways in a gradient manner from the Golgi apparatus to the plasma membrane. Moreover, BDCPs localize to a diverse set of vesicles positive for a variety of Rab small GTPases.
In the thesis it was shown how the N-terminal α-solenoid and concanavalin A-like domains in the typical BDCPs facilitate their membrane localization. The PH-BEACH-WD40 domain assembly was found to bind to cytosolic tails of transmembrane proteins such as CTLA4. The presence of both an α-solenoid region and a WD40 domain indicate that BDCPs function as novel coatomers involved in trafficking of transmembrane proteins, similarly to COPI, COPII, and clathrin.
The structure of NBEAL2 was solved through Cryo-EM at a resolution of 6.6 Å. This model corresponded well with the predicted AlphaFold3 models, thus validating the theoretical models. Disease-associated point mutants in the N-terminal region of NBEAL2 were found to disrupt the specific protein localization, whereas the C-terminal mutants are hypothesized to affect its binding to and sorting of transmembrane cargo.
In conclusion, the BDCPs were found to function as potential coatomers and play important roles in intracellular sorting and trafficking of transmembrane proteins. BDCPs are linked to several diseases and conditions, and further elucidation of the function of these proteins will be important in helping patients and increase our understanding of the complex cellular sorting and trafficking systems.
Additional information
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