Auxiliary barrier function of karyopherins at the Nuclear Pore Complex

Kalita, Joanna Małgorzata. Auxiliary barrier function of karyopherins at the Nuclear Pore Complex. 2023, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/96055/

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Nuclear pore complexes (NPCs) are highly selective gateways that mediate nucleocytoplasmic transport (NCT) in eukaryotic cells. Recent discoveries have shown that leaky NPCs and defective NCT are linked to aging, neurodegenerative disorders, and viral pathogenesis. Nevertheless, their exact underlying cause(s) are unknown, reflecting an incomplete understanding of the key regulatory aspects of NPC function. At the heart of this problem lies the NPC permeability barrier, whose behavior has been largely modeled after the in vitro behavior of intrinsically disordered proteins termed phenylalanine-glycine nucleoporins (FG Nups). Nonetheless, this view is puzzling since certain key soluble nuclear transport receptors called β-karyopherins (Kapβs) are strongly enriched within NPCs in vivo.
The experimental results reported in this thesis show that two major Kapβs, Kapβ1 (importinβ) and CRM1 (exportin1) are essential for fortifying the NPC permeability barrier against defective NCT and nuclear leakage in vivo. A further surprise is that CRM1 partially compensates for Kapβ1 upon depletion of the latter from the NPC, which suggests that Kapβ1 and CRM1 engage in a balancing act to reinforce NPC barrier function. Combining ex vivo and biophysical experimentation, as well as computational modeling, we further show how the occupancy of different Kapβs at the NPC is constrained by their size, cellular abundance, binding avidity to the FG Nups, and competition with other Kapβs, such as demonstrated for another Kapβ, Importin-5 (Imp5). Taken together, these findings provide important intersection points and raise new questions with respect to the causes of NPC leakage and defective NCT in aging and cellular pathologies.
Advisors:Lim, Roderick Y.H.
Committee Members:Affolter, Markus and Veenhoff, Liesbeth
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Nanobiology Argovia (Lim)
UniBasel Contributors:Lim, Roderick Y.H. and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15202
Thesis status:Complete
Number of Pages:xiii, 114
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss152024
edoc DOI:
Last Modified:14 Dec 2023 05:30
Deposited On:13 Dec 2023 14:22

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