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The Architecture of the Nuclear Pore Complex


Lin, Daniel Hanyang (2017) The Architecture of the Nuclear Pore Complex. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z98P5XK8.


Nucleocytoplasmic transport, the regulated trafficking of macromolecules in and out of the nucleus, occurs primarily through nuclear pore complexes (NPCs). NPCs are massive macromolecular machines embedded in the nuclear envelope which generate ~40 nanometer transport channels to facilitate transport. Because of its size and complexity (~1000 subunits, ~120 MDa), the structure of the NPC has remained poorly understood. This thesis presents a bottom-up approach to understanding the structure and function of the NPC through reconstitution of the proteins and structural and biochemical studies. The first three chapters present work towards determining the composite structure of the symmetric core of the NPC. X-ray crystal structures are described for many of the components of the symmetric core. This includes a heterohexameric coat nucleoporin complex containing Nup120, Nup85, Nup145C, Sec13, Seh1, and Nup84, revealing how these proteins assemble into one of the main subcomplexes in the NPC. Reconstitution of the symmetric core components and analysis of the protein-protein interaction between the components provides a detailed biochemical map for the protein interaction network in the NPC. X-ray crystal structures of overlapping fragments facilitate the generation of accurate atomic model for full-length proteins. An iterative, sequential docking approach is developed to dock these models into a cryoelectron tomographic reconstruction of the human NPC, yielding a composite model for the structure of the symmetric core of the NPC. In the next two chapters, this analysis is extended to the cytoplasmic-specific decorations of the NPC. The structure of the C-terminal domain of Nup358 is reported and its catalytic activity is described. Lastly, reconstitution of human DDX19 activation by the NPC reveals mechanistic insight into how the NPC directly regulates the last step of mRNA export.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:X-ray crystallography, nucleocytoplasmic transport, mRNA export, enzymology, biochemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Awards:Harold M. Weintraub Award, Herbert Newby McCoy Award
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Hoelz, Andre
Thesis Committee:
  • Shan, Shu-ou (chair)
  • Clemons, William M.
  • Rees, Douglas C.
  • Hoelz, Andre
Defense Date:2 June 2017
Funding AgencyGrant Number
Record Number:CaltechTHESIS:06092017-125142341
Persistent URL:
Related URLs:
URLURL TypeDescription 1: Architecture of the nuclear pore complex coat 2: Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins 3: Architecture of the symmetric core of the nuclear pore 4: Structural and functional analysis of the C-terminal domain of Nup358/RanBP2
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10333
Deposited By: Daniel Lin
Deposited On:09 Jun 2017 23:41
Last Modified:04 Oct 2019 00:17

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