Crystal Structure of the N-Terminal Domain of Nup358/RanBP2

Kassube, Susanne A.; Stuwe, T.; Lin, Daniel H.; Antonuk, C. Danielle; Napetschnig, Johanna; Blobel, Günter; Hoelz, André

doi:10.1016/j.jmb.2012.08.026

Cited by 37 publications

(39 citation statements)

References 57 publications

(68 reference statements)

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“…Because we did not discern any ERG and hnRNPA2/B1 changes in the outer retina, the most likely scenario is that a decrease of hnRNPA2/B1 levels in the inner retina upon loss of Ranbp2 PPIase activity selectively potentiates the activity of hnRNPA2/B1 leading to a shorter dark-adapted VEP latency. Furthermore, the following observations also support the notion that changes in hnRNPA2/B1 proteostasis are a major contributor to the reduced latency of dark-adapted VEPs: (i) Ranbp2 is a docking site for the nuclear export receptor, CRM1/ exportin-1 (63); (ii) Ranbp2 affects selectively the levels of the RNA-binding proteins, hnRNPA2/B1, as shown here; (iii) Ranbp2 binds single-stranded RNA (126); and (iv) Ranbp2 stimulates the export of mRNA and translation of endoplasmic reticulum-targeted and likely mitochondrially targeted proteins in cell culture (123,124). Finally, although no PPIase activity was detected consistently in vitro with CY R2944A , it is arguably possible that Tg-Ranbp2 R2944A-HA ::Ranbp2 Ϫ/Ϫ mice may still harbor vanishingly low levels of CY PPIase activity.…”

Section: Discussionsupporting

confidence: 79%

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

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Background: Cyclophilins harbor ill-defined chaperone and prolyl isomerase activities toward physiological substrates. Results: Nonoverlapping chaperone or prolyl isomerase activity loss of Ran-binding protein 2 (Ranbp2) cyclophilin domain triggers unique impairments of proteostasis in distinct cell types and ubiquitin-proteasome system. Conclusion: Ranbp2 cyclophilin subdomains present discriminating physiological activities toward substrates or regulation of ubiquitin-proteasome system. Significance: Ranbp2-mediated mechanistic links in proteostasis with physiological and therapeutic relevance are uncovered.The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and a conformational switch in protein function. Cyclophilins are also chaperones. Noncatalytic mutations affecting the only cyclophilins with known but distinct physiological substrates, the Drosophila NinaA and its mammalian homolog, cyclophilin-B, impair opsin biogenesis and cause osteogenesis imperfecta, respectively. However, the physiological roles and substrates of most cyclophilins remain unknown. It is also unclear if PPIase and chaperone activities reflect distinct cyclophilin properties. To elucidate the physiological idiosyncrasy stemming from potential cyclophilin functions, we generated mice lacking endogenous Ran-binding protein-2 (Ranbp2) and expressing bacterial artificial chromosomes of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2 WT-HA ) or without PPIase activities (Tg-Ranbp2 R2944A-HA ). The transgenic lines exhibit unique effects in proteostasis. Either line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in cone photoreceptors but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, STAT3/STAT5. Peptidyl cis-trans-prolyl isomerization is a rate-limiting step in protein folding (1-3). The catalysis of the cis-trans interconversion of the peptidyl-prolyl isomers is catalyzed by peptidylprolyl cis-trans isomerases (PPIase) 5 (4 -6). PPIases compose three families of structurally unrelated proteins, the cyclophilins (CyP), FK506-binding proteins (FKBP), and parvulins (7). * This work was supported, in whole or in part, by National Institutes of Health Grants EY019492, GM083165, and GM083165-03S1 (to P. A. F.), 2P30-EY005722 (to Duke University Eye Center), and 5P30NS061789 (to Duke Neurotransgenic Laboratory). This work was also supported by the Foundation Fighting CyPs and FKBPs are designated also as immunophilins, because they mediate immunosuppression (8,9). This effect is achieved by a gain-of-function mechanism upon binding of the immunosuppressive metabolites, cyclosporin A (CsA) or FK506, to the PPIase active site and formation of a ternary complex with the serine/threonine phosphatase, calcineurin, whose sequestration and inhibition prevents the dephosphorylation and activation of the nuclear factor for activation of T-cells (9 -12). Howe...

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Section: Discussionsupporting

confidence: 79%

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

View full text Add to dashboard Cite

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“…6). Alternatively, other nearby stopover sites might be available (e.g., in the form of the recently identified RNA binding site on Nup358) (27) to assure that ratcheting of mRNA (13,14) across the central channel of the NPC does not fail.…”

Section: Discussionmentioning

confidence: 99%

Vesiculoviral matrix (M) protein occupies nucleic acid binding site at nucleoporin pair (Rae1•Nup98)

Quan

Seo

Blobel

et al. 2014

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

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mRNA export factor 1 (Rae1) and nucleoporin 98 (Nup98) are host cell targets for the matrix (M) protein of vesicular stomatitis virus (VSV). How Rae1 functions in mRNA export and how M protein targets both Rae1 and Nup98 are not understood at the molecular level. To obtain structural insights, we assembled a 1:1:1 complex of M•Rae1•Nup98 and established a crystal structure at 3.15-Å resolution. We found that the M protein contacts the Rae1•Nup98 heterodimer principally by two protrusions projecting from the globular domain of M like a finger and thumb. Both projections clamp to the side of the β-propeller of Rae1, with the finger also contacting Nup98. The most prominent feature of the finger is highly conserved Methionine 51 (Met51) with upstream and downstream acidic residues. The complementary surface on Rae1 displays a deep hydrophobic pocket, into which Met51 fastens like a bolt, and a groove of basic residues on either side, which bond to the acidic residues of the finger. Notably, the M protein competed for in vitro binding of various oligonucleotides to Rae1•Nup98. We localized this competing activity of M to its finger using a synthetic peptide. Collectively, our data suggest that Rae1 serves as a binding protein for the phosphate backbone of any nucleic acid and that the finger of M mimics this ligand. In the context of mRNA export, we propose that a given mRNA segment, after having been deproteinated by helicase, is transiently reproteinated by Nup98-tethered Rae1. We suggest that such repetitive cycles provide cytoplasmic stopover sites required for ratcheting mRNA across the nuclear pore.phosphate backbone binding | M protein mimicry | mRNP export

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“…Structural studies provided key insights into the architecture and function of the coat and channel nucleoporins, as well as the interactions of the cytoplasmic filament nucleoporins with the mRNA export machinery (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)). …”

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confidence: 99%

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

Stuwe

Lin

Collins

et al. 2014

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

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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.X-ray crystallography | site-directed mutagenesis | mega assembly | structure-function analysis

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Crystal Structure of the N-Terminal Domain of Nup358/RanBP2

Cited by 37 publications

References 57 publications

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Vesiculoviral matrix (M) protein occupies nucleic acid binding site at nucleoporin pair (Rae1•Nup98)

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

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