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Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins

Stuwe, Tobias and Lin, Daniel H. and Collins, Leslie N. and Hurt, Ed and Hoelz, André (2014) Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins. Proceedings of the National Academy of Sciences of the United States of America, 111 (7). pp. 2530-2535. ISSN 0027-8424. PMCID PMC3932873. doi:10.1073/pnas.1311081111.

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Nucleocytoplasmic transport is facilitated by nuclear pore complexes (NPCs), which are massive proteinaceous transport channels embedded in the nuclear envelope. Nup192 is a major component of an adaptor nucleoporin subcomplex proposed to link the NPC coat with the central transport channel. Here, we present the structure of the ∼110-kDa N-terminal domain (NTD) of Nup192 at 2.7-Å resolution. The structure reveals an open ring-shaped architecture composed of Huntingtin, EF3, PP2A, and TOR1 (HEAT) and Armadillo (ARM) repeats. A comparison of different conformations indicates that the NTD consists of two rigid halves connected by a flexible hinge. Unexpectedly, the two halves of the ring are structurally related to karyopherin-α (Kap-α) and β-karyopherin family members. Biochemically, we identify a conserved patch that binds an unstructured segment in Nup53 and show that a C-terminal tail region binds to a putative helical fragment in Nic96. The Nup53 segment that binds Nup192 is a classical nuclear localization-like sequence that interacts with Kap-α in a mutually exclusive and mechanistically distinct manner. The disruption of the Nup53 and Nic96 binding sites in vivo yields growth and mRNA export defects, revealing their critical role in proper NPC function. Surprisingly, both interactions are dispensable for NPC localization, suggesting that Nup192 possesses another nucleoporin interaction partner. These data indicate that the structured domains in the adaptor nucleoporin complex are held together by peptide interactions that resemble those found in karyopherin•cargo complexes and support the proposal that the adaptor nucleoporins arose from ancestral karyopherins.

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URLURL TypeDescription CentralArticle
Hoelz, André0000-0003-1726-0127
Additional Information:© 2014 National Academy of Sciences. Edited by Douglas C. Rees, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, and approved January 13, 2014 (received for review June 11, 2013). Author contributions: T.S., D.H.L., and A.H. designed research; T.S., D.H.L., L.N.C., and A.H. performed research; T.S., D.H.L., E.H., and A.H. contributed new reagents/analytic tools; T.S., D.H.L., L.N.C., and A.H. analyzed data; and T.S., D.H.L., and A.H. wrote the paper. The authors declare no conflict of interest. We thank members of the A.H. laboratory, Alina Patke, and Yunji Wu for critical reading of the manuscript; David King for MS analysis; Jens Kaiser and the scientific staff of Stanford Synchrotron Radiation Lightsource (SSRL) beam line 12-2 for their support with X-ray diffraction measurements; the University of Colorado Biophysics Core for assistance with ITC measurements; and Elena Conti for material. We acknowledge the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi–Aventis Bioengineering Research Program for their support of the Molecular Observatory at the California Institute of Technology. The SSRL is supported by the Department of Energy and by the National Institutes of Health (NIH). T.S. is supported by a Deutsche Forschungsgemeinschaft (DFG) postdoctoral fellowship. D.H.L. is supported by an NIH Research Service Award (Grant 5 T32 GM07616). A.H. was supported by the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Sanofi-Aventis Bioengineering Research ProgramUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)UNSPECIFIED
NIH Predoctoral Fellowship5 T32 GM07616
V Foundation for Cancer ResearchUNSPECIFIED
Edward Mallinckrodt, Jr. FoundationUNSPECIFIED
Sidney Kimmel Foundation for Cancer ResearchUNSPECIFIED
Subject Keywords:X-ray crystallography; site-directed mutagenesis; mega assembly; structure-function analysis
Issue or Number:7
PubMed Central ID:PMC3932873
Record Number:CaltechAUTHORS:20140210-133852763
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Official Citation:Tobias Stuwe, Daniel H. Lin, Leslie N. Collins, Ed Hurt, and André Hoelz Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins PNAS 2014 ; published ahead of print February 6, 2014, doi:10.1073/pnas.1311081111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43751
Deposited By: Ruth Sustaita
Deposited On:10 Feb 2014 22:09
Last Modified:10 Nov 2021 16:42

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