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A Role for Pom121 in Linking the Nuclear Pore Complex Membrane Scaffold to the Pore Membrane Domain Open Access


Other title
Nuclear Pore Complex
Nuclear Envelope
Type of item
Degree grantor
University of Alberta
Author or creator
Mitchell, Jana M
Supervisor and department
Wozniak, Rick (Cell Biology)
Examining committee member and department
Underhill, Alan (Oncology)
Melancon, Paul (Cell Biology)
Monpetit, Ben (Cell Biology)
Chook, Yuh Min (Pharmacology, Biophysics)
Department of Cell Biology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
A key step in the evolutionary progression from prokaryote to eukaryote was development of the endomembrane system, including encapsulation of genetic material by the impermeable nuclear envelope (NE). Trafficking of macromolecules between cytoplasmic and nuclear compartments required the concomitant evolution of nuclear pore complexes (NPCs), sophisticated transport channels embedded within the NE. NPCs are comprised of a highly specialized subset of proteins termed nucleoporins (Nups). Nups that localize to the pore membrane domain (POM) of the NE stabilize membrane curvature resulting from circumferential fusion of NE membrane leaflets to form the pore in which the NPC resides. The architecture of the membrane-scaffolding NPC coat, and importantly, how this coat interfaces the POM, is unknown. We examined the interactions between NPC scaffold proteins Nup155 and Nup160 with the POM. We show that depletion of Nup155 causes alterations in NE structure, including a dramatic decrease in NPC numbers. We describe novel interactions between β-propeller domains of Nup155 and Nup160 with the transmembrane Nup (Pom) Pom121, and suggest that these interactions are critical for NPC assembly. To better define a role for scaffold Nups in NPC structural organization, we focused on determining atomic structures of Nups comprising the conserved Nup107-160 scaffold complex. We present the crystal structure of the Schizosaccharomyces pombe (Sp) Nup1201-950-Nup37 heterodimer (orthologous to metazoan Nup160 and Nup37), and demonstrate that capture of Nup37 within the  scaffold coat co-evolved with the acquisition of an α-helical domain within the β- propeller of Nup160 orthologues. We demonstrated that this interaction is conserved in metazoan cells, and extended our analysis to investigate the association of additional scaffold β-propellers with Pom121. We uncovered novel interactions between Pom121 with Nup37 and Nup43, expanding the Pom121 interactome to include four β-propeller proteins of the NPC membrane coat. We envisage a model whereby Pom121 extends from the NE towards the NPC central channel, linking structural modules of the NPC through interactions with β- propeller domains of Nup37, Nup43, Nup155 and Nup160. These interactions are likely regulated during NPC assembly, and plasticity of the Pom121 interactome may facilitate the reversible dilation of the NPC transport channel in response to cellular metabolic demands.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Mitchell, J.M., J. Mansfeld, J. Capitanio, U. Kutay, and R.W. Wozniak. 2010. Pom121 links two essential subcomplexes of the nuclear pore complex core to the membrane. The Journal of Cell Biology. 191:505-521.X.Liu, J.M. Mitchell, R.W. Wozniak, G. Blobel, and J. Fan. 2012. Structural evolution of the membrane-coating module of the nuclear pore complex. Proceedings of the National Academy of Sciences of the United States of America. 109:16498-16503.

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