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Molecular Basis for the Anchoring of Proto-Oncoprotein Nup98 to the Cytoplasmic Face of the Nuclear Pore Complex

Stuwe, Tobias and von Borzyskowski, Lennart Schada and Davenport, Andrew M. and Hoelz, André (2012) Molecular Basis for the Anchoring of Proto-Oncoprotein Nup98 to the Cytoplasmic Face of the Nuclear Pore Complex. Journal of Molecular Biology, 419 (5). pp. 330-346. ISSN 0022-2836. PMCID PMC4226653. https://resolver.caltech.edu/CaltechAUTHORS:20120711-141315516

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Abstract

The cytoplasmic filament nucleoporins of the nuclear pore complex (NPC) are critically involved in nuclear export and remodeling of mRNA ribonucleoprotein particles and are associated with various human malignancies. Here, we report the crystal structure of the Nup98 C-terminal autoproteolytic domain, frequently missing from leukemogenic forms of the protein, in complex with the N-terminal domain of Nup82 and the C-terminal tail fragment of Nup159. The Nup82 β propeller serves as a noncooperative binding platform for both binding partners. Interaction of Nup98 with Nup82 occurs through a reciprocal exchange of loop structures. Strikingly, the same Nup98 groove promiscuously interacts with Nup82 and Nup96 in a mutually excusive fashion. Simultaneous disruption of both Nup82 interactions in yeast causes severe defects in mRNA export, while the severing of a single interaction is tolerated. Thus, the cytoplasmic filament network of the NPC is robust, consistent with its essential function in nucleocytoplasmic transport.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.jmb.2012.03.024DOIArticle
http://www.sciencedirect.com/science/article/pii/S0022283612002987PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226653PubMed CentralArticle
Additional Information:© 2012 Elsevier. Received 15 February 2012; received in revised form 22 March 2012; accepted 26 March 2012. Available online 2 April 2012. Edited by I. Wilson. We thank Alina Patke for critical reading of the manuscript, the members of the Hoelz Laboratory for discussions, Stephanie Etherton for help with editing of the manuscript, Evelyn Stuwe for help with microscopy, and David King for mass spectrometry analysis. We thank Jens Kaiser and the scientific staff of SSRL beamline 12-2 for their support with X-ray diffraction measurements. We acknowledge the Gordon and Betty Moore Foundation for their support of the Molecular Observatory at the California Institute of Technology. The operations at the SSRL are supported by the Department of Energy and by the National Institutes of Health. L.S.v.B. was supported by a fellowship of the German National Merit Foundation, A.M.D. was supported by National Institutes of Health Research Service Award (5 T32 GM07616), and A.H. was supported by the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, by the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and by the Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research. Author Contributions: T.T.S. and A.H. designed research; T.T.S., L.S.v.B., A.M.D., and A.H. carried out research; T.T.S., L.S.v.B., A.M.D., and A.H. analyzed data; and T.T.S., A.M.D., and A.H. prepared the figures and wrote the manuscript. The authors declare that they have no conflict of interest.
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
German National Merit Foundation UNSPECIFIED
NIH5 T32 GM07616
V Foundation for Cancer ResearchUNSPECIFIED
Edward Mallinckrodt, Jr. FoundationUNSPECIFIED
Sidney Kimmel Foundation for Cancer ResearchUNSPECIFIED
Subject Keywords:macromolecular assembly; evolutionary conservation; mRNA export; Nup98 leukemias; X-ray crystallography
Other Numbering System:
Other Numbering System NameOther Numbering System ID
Protein Data Bank Accession No.3TKN
Issue or Number:5
PubMed Central ID:PMC4226653
Record Number:CaltechAUTHORS:20120711-141315516
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120711-141315516
Official Citation:Tobias Stuwe, Lennart Schada von Borzyskowski, Andrew M. Davenport, André Hoelz, Molecular Basis for the Anchoring of Proto-Oncoprotein Nup98 to the Cytoplasmic Face of the Nuclear Pore Complex, Journal of Molecular Biology, Volume 419, Issue 5, 22 June 2012, Pages 330-346, ISSN 0022-2836, 10.1016/j.jmb.2012.03.024. (http://www.sciencedirect.com/science/article/pii/S0022283612002987)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:32364
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:11 Jul 2012 21:52
Last Modified:03 Oct 2019 04:00

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