scholarly journals Two Tails for Neurofibromin: A Tale of Two Microtubule-Associated Proteins

2021 ◽  
Author(s):  
Charoula Peta ◽  
Emmanouella Tsirimonaki ◽  
Constantinos Fedonidis ◽  
Xeni Koliou ◽  
Nikos Sakellaridis ◽  
...  
Keyword(s):  
Splice Variants ◽  
Point Mutations ◽  
Neurofibromatosis Type ◽  
Nuclear Localization Sequence ◽  
Major Theme ◽  
Patient Counselling ◽  
Associated Proteins ◽  
Localization Sequence ◽  
Specific Alternative ◽  
Cell Type Specific

Neurofibromatosis type 1, NF-1, is a common monogenic (NF1) disease, characterized by highly variable clinical presentation and high predisposition for tumors, especially those of astrocytic origin (low- to high-grade gliomas). Unfortunately, very few genotype–phenotype correlations have been possible, and the numerous identified mutations do not offer help for prognosis and patient counselling. Whole gene deletion in animals does not successfully model the disease, as NF-1 cases caused by point mutations could be differentially affected by cell type-specific alternative splice variants of NF1. In this chapter, we will discuss the differential Microtubule-Associated-Protein (MAP) properties of NLS or ΔNLS neurofibromins, produced by the alternatively splicing of exon 51, which also contains a Nuclear Localization Sequence (NLS), in the assembly of the mitotic spindle and in faithful genome transmission. We will also commend on the major theme that emerges about NLS-containing tumor suppressors that function as mitotic MAPs.

scholarly journals Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2348
Author(s):  
Charoula Peta ◽  
Emmanouella Tsirimonaki ◽  
Dimitris Samouil ◽  
Kyriaki Georgiadou ◽  
Dimitra Mangoura
Keyword(s):  
Chromosome Segregation ◽  
Tumor Development ◽  
Abnormal Chromosome ◽  
Nuclear Localization Sequence ◽  
Neural Cells ◽  
Mitotic Spindles ◽  
Critical Function ◽  
Chromosome Congression ◽  
Associated Proteins ◽  
Localization Sequence

Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions.

scholarly journals Proteins Connecting the Nuclear Pore Complex with the Nuclear Interior

1999 ◽  
Vol 144 (5) ◽  
pp. 839-855 ◽  
Author(s):  
Caterina Strambio-de-Castillia ◽  
Günter Blobel ◽  
Michael P. Rout
Keyword(s):  
Nuclear Pore Complex ◽  
Nuclear Import ◽  
Nuclear Localization Sequence ◽  
Nuclear Pore ◽  
Reporter Protein ◽  
Double Deletion ◽  
Large Structures ◽  
Associated Proteins ◽  
Localization Sequence ◽  
Transport Factors

While much has been learned in recent years about the movement of soluble transport factors across the nuclear pore complex (NPC), comparatively little is known about intranuclear trafficking. We isolated the previously identified Saccharomyces protein Mlp1p (myosin-like protein) by an assay designed to find nuclear envelope (NE) associated proteins that are not nucleoporins. We localized both Mlp1p and a closely related protein that we termed Mlp2p to filamentous structures stretching from the nucleoplasmic face of the NE into the nucleoplasm, similar to the homologous vertebrate and Drosophila Tpr proteins. Mlp1p can be imported into the nucleus by virtue of a nuclear localization sequence (NLS) within its COOH-terminal domain. Overexpression experiments indicate that Mlp1p can form large structures within the nucleus which exclude chromatin but appear highly permeable to proteins. Remarkably, cells harboring a double deletion of MLP1 and MLP2 were viable, although they showed a slower net rate of active nuclear import and faster passive efflux of a reporter protein. Our data indicate that the Tpr homologues are not merely NPC-associated proteins but that they can be part of NPC-independent, peripheral intranuclear structures. In addition, we suggest that the Tpr filaments could provide chromatin-free conduits or tracks to guide the efficient translocation of macromolecules between the nucleoplasm and the NPC.

scholarly journals Prm3p Is a Pheromone-induced Peripheral Nuclear Envelope Protein Required for Yeast Nuclear Fusion

2009 ◽  
Vol 20 (9) ◽  
pp. 2438-2450 ◽  
Author(s):  
Shu Shen ◽  
Cynthia E. Tobery ◽  
Mark D. Rose
Keyword(s):  
Nuclear Envelope ◽  
Membrane Fusion ◽  
Nuclear Membrane ◽  
Protein Function ◽  
Spindle Pole Body ◽  
Point Mutations ◽  
Spindle Pole ◽  
Nuclear Localization Sequence ◽  
Yeast Saccharomyces Cerevisiae ◽  
Localization Sequence

Nuclear membrane fusion is the last step in the mating pathway of the yeast Saccharomyces cerevisiae. We adapted a bioinformatics approach to identify putative pheromone-induced membrane proteins potentially required for nuclear membrane fusion. One protein, Prm3p, was found to be required for nuclear membrane fusion; disruption of PRM3 caused a strong bilateral defect, in which nuclear congression was completed but fusion did not occur. Prm3p was localized to the nuclear envelope in pheromone-responding cells, with significant colocalization with the spindle pole body in zygotes. A previous report, using a truncated protein, claimed that Prm3p is localized to the inner nuclear envelope. Based on biochemistry, immunoelectron microscopy and live cell microscopy, we find that functional Prm3p is a peripheral membrane protein exposed on the cytoplasmic face of the outer nuclear envelope. In support of this, mutations in a putative nuclear localization sequence had no effect on full-length protein function or localization. In contrast, point mutations and deletions in the highly conserved hydrophobic carboxy-terminal domain disrupted both protein function and localization. Genetic analysis, colocalization, and biochemical experiments indicate that Prm3p interacts directly with Kar5p, suggesting that nuclear membrane fusion is mediated by a protein complex.

307 Is nuclear accumulation of interferon regulatory factor (IRF)-3 dependent on a functional nuclear localization sequence?

Cytokine ◽  
2008 ◽  
Vol 43 (3) ◽  
pp. 316
Author(s):  
Annie Bibeau-Poirier ◽  
Jean-François Clément ◽  
Rongtuan Lin ◽  
Marc J. Servant
Keyword(s):  
Nuclear Localization ◽  
Interferon Regulatory Factor ◽  
Nuclear Accumulation ◽  
Nuclear Localization Sequence ◽  
Regulatory Factor ◽  
Localization Sequence

scholarly journals Identification of a nuclear localization sequence within the structure of the human interleukin-1 alpha precursor.

1993 ◽  
Vol 268 (29) ◽  
pp. 22100-22104
Author(s):  
J.H. Wessendorf ◽  
S Garfinkel ◽  
X Zhan ◽  
S Brown ◽  
T Maciag
Keyword(s):  
Nuclear Localization ◽  
Interleukin 1 ◽  
Nuclear Localization Sequence ◽  
Localization Sequence

The nuclear localization sequence of the epigenetic factor RYBP binds to human importin α3

2021 ◽  
pp. 140670
Author(s):  
José L. Neira ◽  
Ana Jiménez-Alesanco ◽  
Bruno Rizzuti ◽  
Adrián Velazquez-Campoy
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Sequence ◽  
Epigenetic Factor ◽  
Localization Sequence

scholarly journals Tools for the Recognition of Sorting Signals and the Prediction of Subcellular Localization of Proteins From Their Amino Acid Sequences

2020 ◽  
Vol 11 ◽  
Author(s):  
Kenichiro Imai ◽  
Kenta Nakai
Keyword(s):  
Amino Acid ◽  
Subcellular Localization ◽  
Amino Acid Sequences ◽  
Additional Information ◽  
Sorting Signals ◽  
Specific Alternative ◽  
Cell Type Specific ◽  
Future Direction ◽  
The Impact ◽  
New Algorithms

At the time of translation, nascent proteins are thought to be sorted into their final subcellular localization sites, based on the part of their amino acid sequences (i.e., sorting or targeting signals). Thus, it is interesting to computationally recognize these signals from the amino acid sequences of any given proteins and to predict their final subcellular localization with such information, supplemented with additional information (e.g., k-mer frequency). This field has a long history and many prediction tools have been released. Even in this era of proteomic atlas at the single-cell level, researchers continue to develop new algorithms, aiming at accessing the impact of disease-causing mutations/cell type-specific alternative splicing, for example. In this article, we overview the entire field and discuss its future direction.

Elongator's toxin-target (TOT) function is nuclear localization sequence dependent and suppressed by post-translational modification

2003 ◽  
Vol 49 (5) ◽  
pp. 1297-1307 ◽  
Author(s):  
Lars Fichtner ◽  
Daniel Jablonowski ◽  
Angelika Schierhorn ◽  
Hiroko K. Kitamoto ◽  
Michael J. R. Stark ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Sequence ◽  
Post Translational Modification ◽  
Sequence Dependent ◽  
Localization Sequence

Novel properties of the protein kinase CK2-site-regulated nuclear- localization sequence of the interferon-induced nuclear factor IFI 16

2000 ◽  
Vol 353 (1) ◽  
pp. 69-77 ◽  
Author(s):  
Lyndall J. BRIGGS ◽  
Ricky W. JOHNSTONE ◽  
Rachel M. ELLIOT ◽  
Chong-Yun XIAO ◽  
Michelle DAWSON ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Localization ◽  
Nuclear Import ◽  
Protein Kinase Ck2 ◽  
Protein Import ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Nuclear Localization Sequence ◽  
Localization Sequence ◽  
Kinase Ck2

Members of the interferon-induced class of nuclear factors possess a putative CcN motif, comparable with that within proteins such as the simian virus 40 large tumour antigen (T-ag), which confers phosphorylation-mediated regulation of nuclear-localization sequence (NLS)-dependent nuclear import. Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). The IFI 16 NLS, however, has novel properties, conferring ATP-dependent nuclear import completely independent of cytosolic factors, as well as binding to nuclear components. The IFI 16 NLS is not recognized with high affinity by the NLS-binding importin heterodimer, and transport mediated by it is insensitive to non-hydrolysable GTP analogues. The IFI 16 NLS thus mediates nuclear import through a pathway completely distinct from that of conventional NLSs, such as that of T-ag, but intriguingly resembling that of the NLS of the HIV-1 transactivator protein Tat. Since the IFI 16 CK2 site enhances nuclear import through facilitating binding to nuclear components, this represents a novel mechanism by which the site regulates nuclear-protein import, and constitutes a difference between the IFI 16 and Tat NLSs that may be of importance in the immune response.

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