Crystal structure of the N-terminal domain of the human protooncogene Nup214/CAN

Napetschnig, Johanna; Blobel, Günter; Hoelz, André

doi:10.1073/pnas.0610828104

Cited by 58 publications

(51 citation statements)

References 37 publications

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“…6. We can rule out that the LMBinhibited CRM1 competes with virion for docking at the NPC, consistent with the notion that the phenylalanine-glycine repeats in the N-terminal domain of Nup214 are used for adenovirus binding but not for CRM1 interactions (Cassany et al, 2014;Fornerod et al, 1997b;Napetschnig et al, 2007).…”

Section: Discussionmentioning

confidence: 91%

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Wang

Burckhardt

Yakimovich

et al. 2017

Journal of Cell Science

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Transport of large cargo through the cytoplasm requires motor proteins and polarized filaments. Viruses that replicate in the nucleus of post-mitotic cells use microtubules and the dynein-dynactin motor to traffic to the nuclear membrane and deliver their genome through nuclear pore complexes (NPCs) into the nucleus. How virus particles (virions) or cellular cargo are transferred from microtubules to the NPC is unknown. Here, we analyzed trafficking of incoming cytoplasmic adenoviruses by single-particle tracking and superresolution microscopy. We provide evidence for a regulatory role of CRM1 (chromosome-region-maintenance-1; also known as XPO1, exportin-1) in juxta-nuclear microtubule-dependent adenovirus transport. Leptomycin B (LMB) abolishes nuclear targeting of adenovirus. It binds to CRM1, precludes CRM1-cargo binding and blocks signal-dependent nuclear export. LMB-inhibited CRM1 did not compete with adenovirus for binding to the nucleoporin Nup214 at the NPC. Instead, CRM1 inhibition selectively enhanced virion association with microtubules, and boosted virion motions on microtubules less than ∼2 µm from the nuclear membrane. The data show that the nucleus provides positional information for incoming virions to detach from microtubules, engage a slower microtubule-independent motility to the NPC and enhance infection.

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Section: Discussionmentioning

confidence: 91%

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Wang

Burckhardt

Yakimovich

et al. 2017

Journal of Cell Science

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“…This finding then raises the question, at which stage the various assembly states occur: during synthesis and/or storage in the cytoplasm, during NPC assembly, or in the assembled NPC as functional intermediates. For example, Nup84 binding to the Nup145C homo-dimerization region in a chaperone-like fashion may be required to prevent oligomerization of the heptamer in the cytoplasm, and may be altered by adjacent nucleoporins during assembly and/or function of the NPC (36). Alternatively, the Nup145C⅐Nup84 interaction could be required for capping of the coat for the nuclear pore membrane at the peripheral rings (26,27,34).…”

Section: Discussionmentioning

confidence: 99%

Structure of a trimeric nucleoporin complex reveals alternate oligomerization states

Nagy

Hsia

Debler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The heptameric Nup84 complex constitutes an evolutionarily conserved building block of the nuclear pore complex. Here, we present the crystal structure of the heterotrimeric Sec13⅐Nup145C⅐Nup84 complex, the centerpiece of the heptamer, at 3.2-Å resolution. Nup84 forms a U-shaped ␣-helical solenoid domain, topologically similar to two other members of the heptamer, Nup145C and Nup85. The interaction between Nup84 and Nup145C is mediated via a hydrophobic interface located in the kink regions of the two solenoids that is reinforced by additional interactions of two long Nup84 loops. The Nup84 binding site partially overlaps with the homo-dimerization interface of Nup145C, suggesting competing binding events. Fitting of the elongated Z-shaped heterotrimer into electron microscopy (EM) envelopes of the heptamer indicates that structural changes occur at the Nup145C⅐Nup84 interface. Docking the crystal structures of all heptamer components into the EM envelope constitutes a major advance toward the completion of the structural characterization of the Nup84 complex.electron microscopy docking ͉ nuclear pore complex ͉ protein-protein interaction ͉ X-ray crystallography ͉ binding promiscuity

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“…S3B). For each mutant, a stretch of 5 consecutive residues was deleted from the solvent-exposed part of the 6D7A loop, as seen in the Nup214 NTD crystal structure (14). Again, the behavior of all 3 mutants on a gel filtration column was indistinguishable from that of the wild-type protein.…”

Section: Nup214mentioning

confidence: 99%

“…The localization of Ddx19 to the cytoplasmic side of the NPC has been shown to be dependent on the Nup214 NTD (8). Previously, we solved the structure of the human Nup214 NTD that revealed a ␤-propeller domain and suggested several possible protein-protein interaction surfaces, including the 45-residue C-terminal extension (CTE) and the conserved interblade connector 6D7A (14).…”

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confidence: 99%

Structural and functional analysis of the interaction between the nucleoporin Nup214 and the DEAD-box helicase Ddx19

Napetschnig

Kassube

Debler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Key steps in the export of mRNA from the nucleus to the cytoplasm are the transport through the nuclear pore complex (NPC) and the subsequent remodeling of messenger RNA-protein (mRNP) complexes that occurs at the cytoplasmic side of the NPC. Crucial for these events is the recruitment of the DEAD-box helicase Ddx19 to the cytoplasmic filaments of the NPC that is mediated by the nucleoporin Nup214. Here, we present the crystal structure of the Nup214 N-terminal domain in complex with Ddx19 in its ADPbound state at 2.5 Å resolution. Strikingly, the interaction surfaces are not only evolutionarily conserved but also exhibit strongly opposing surface potentials, with the helicase surface being positively and the Nup214 surface being negatively charged. We speculate that the positively charged surface of the interacting ADP-helicase binds competitively to a segment of mRNA of a linearized mRNP, passing through the NPC on its way to the cytoplasm. As a result, the ADP-helicase would dissociate from Nup214 and replace a single bound protein from the mRNA. One cycle of protein replacement would be accompanied, cooperatively, by nucleotide exchange, ATP hydrolysis, release of the ADP-helicase from mRNA and its rebinding to Nup214. Repeat of these cycles would remove proteins from a mRNP, one at a time, akin to a ratchet mechanism for mRNA export.crystal structure ͉ immunofluorescence localization ͉ mRNA export ͉ mutagenesis ͉ Nup214-helicase complex

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Crystal structure of the N-terminal domain of the human protooncogene Nup214/CAN

Cited by 58 publications

References 37 publications

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Structure of a trimeric nucleoporin complex reveals alternate oligomerization states

Structural and functional analysis of the interaction between the nucleoporin Nup214 and the DEAD-box helicase Ddx19

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