Crystal structure of importin-α bound to a peptide bearing the nuclear localisation signal from chloride intracellular channel protein 4

Abstract Oestrogen receptor-α (ERα) shuttles continuously between the nucleus and the cytoplasm, and functions as an oestrogen-dependent transcription factor in the nucleus and as an active mediator of signalling pathways, such as phosphatidylinositol 3-kinase (PI3K)/AKT, in the cytoplasm. However, little is known regarding the mechanism of ERα nucleocytoplasmic shuttling. In this study, we found that ERα is transported into the nucleus by importin-α/β1. Furthermore, we found that Transportin-2 (TNPO2) is involved in 17β-oestradiol (E2)-dependent cytoplasmic localisation of ERα. Interestingly, it was found that TNPO2 does not mediate nuclear export, but rather is involved in the cytoplasmic retention of ERα via the proline/tyrosine (PY) motifs. Moreover, we found that TNPO2 competitively binds to the basic nuclear localisation signal (NLS) of ERα with importin-α to inhibit importin-α/β-dependent ERα nuclear import. Finally, we confirmed that TNPO2 knockdown enhances the nuclear localisation of wild-type ERα and reduces PI3K/AKT phosphorylation in the presence of E2. These results reveal that TNPO2 regulates nucleocytoplasmic shuttling and cytoplasmic retention of ERα, so that ERα has precise functions depending on the stimulation.

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Targeted cell imaging properties of a deep red luminescent iridium(iii) complex conjugated with a c-Myc signal peptide

Chemical Science ◽

10.1039/c9sc05568a ◽

2020 ◽

Vol 11 (6) ◽

pp. 1599-1606 ◽

Cited By ~ 7

Author(s):

Adam H. Day ◽

Martin H. Übler ◽

Hannah L. Best ◽

Emyr Lloyd-Evans ◽

Robert J. Mart ◽

...

Keyword(s):

Signal Peptide ◽

Cell Imaging ◽

Organometallic Complex ◽

Nuclear Localisation Signal ◽

Nuclear Localisation ◽

Imaging Properties

Visualising a c-Myc nuclear localisation signal peptide using an organometallic complex.

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A Drosophila nuclear localisation signal included in an 18 amino acid fragment from the serendipity δ zinc finger protein

FEBS Letters ◽

10.1016/0014-5793(91)80229-v ◽

1991 ◽

Vol 280 (1) ◽

pp. 167-170 ◽

Cited By ~ 3

Author(s):

Stéphane Noselli ◽

Alain Vincent

Keyword(s):

Amino Acid ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Nuclear Localisation Signal ◽

Nuclear Localisation ◽

Amino Acid Fragment ◽

Finger Protein ◽

Acid Fragment

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Structural insights into the novel ARM-repeat protein CTNNBL1 and its association with the hPrp19–CDC5L complex

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s139900471303318x ◽

2014 ◽

Vol 70 (3) ◽

pp. 780-788 ◽

Cited By ~ 2

Author(s):

Jae-Woo Ahn ◽

Sangwoo Kim ◽

Eun-Jung Kim ◽

Yeo-Jin Kim ◽

Kyung-Jin Kim

Keyword(s):

Crystal Structure ◽

The Novel ◽

Molecular Architecture ◽

Repeat Protein ◽

Binding Partner ◽

Catalytic Activation ◽

Repeat Structure ◽

Repeat Domain ◽

Importin Α ◽

Structural Insights

The hPrp19–CDC5L complex plays a crucial role during human pre-mRNA splicing by catalytic activation of the spliceosome. In order to elucidate the molecular architecture of the hPrp19–CDC5L complex, the crystal structure of CTNNBL1, one of the major components of this complex, was determined. Unlike canonical ARM-repeat proteins such as β-catenin and importin-α, CTNNBL1 was found to contain a twisted and extended ARM-repeat structure at the C-terminal domain and, more importantly, the protein formed a stable dimer. A highly negatively charged patch formed in the N-terminal ARM-repeat domain of CTNNBL1 provides a binding site for CDC5L, a binding partner of the protein in the hPrp19–CDC5L complex, and these two proteins form a complex with a stoichiometry of 2:2. These findings not only present the crystal structure of a novel ARM-repeat protein, CTNNBL1, but also provide insights into the detailed molecular architecture of the hPrp19–CDC5L complex.

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Chloride intracellular channel protein 1 expression in normal and atherosclerotic human arteries. Challenges for a new therapeutic target in atheromatosis.

Atherosclerosis ◽

10.1016/j.atherosclerosis.2021.06.258 ◽

2021 ◽

Vol 331 ◽

pp. e89

Author(s):

A.M. Cimpean ◽

R. Taga

Keyword(s):

Therapeutic Target ◽

Channel Protein ◽

Human Arteries ◽

Intracellular Channel

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Chloride Intracellular Channel Protein 1 and its Role in Neurodegenerative Disorders and Cancerous Tumors

Biochemistry & Analytical Biochemistry ◽

10.4172/2161-1009.1000249 ◽

2016 ◽

Vol s3 ◽

Author(s):

Hillary Nguyen ◽

Antonio Lauto

Keyword(s):

Neurodegenerative Disorders ◽

Channel Protein ◽

Intracellular Channel

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Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer

Cells ◽

10.3390/cells8030281 ◽

2019 ◽

Vol 8 (3) ◽

pp. 281 ◽

Cited By ~ 12

Author(s):

Sundy Yang ◽

Sarah Atkinson ◽

Johanna Fraser ◽

Chunxiao Wang ◽

Belinda Maher ◽

...

Keyword(s):

Analytical Ultracentrifugation ◽

Nonstructural Protein ◽

Effective Vaccine ◽

Nuclear Targeting ◽

Nuclear Localisation ◽

Repeat Domain ◽

Importin Α ◽

Strong Antiviral Activity ◽

Infected Cells

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics.

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