scholarly journals Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target Kapβ2 and dysregulate phase separation of low-complexity domains

2019 ◽  
Author(s):  
Hitoki Nanaura ◽  
Honoka Kawamukai ◽  
Ayano Fujiwara ◽  
Takeru Uehara ◽  
Mari Nakanishi ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Nuclear Transport ◽  
Low Complexity ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion ◽  
Fused In Sarcoma ◽  
Transport Receptors ◽  
Localization Signal ◽  
Competing Interaction

ABSTRACTLow-complexity (LC) domains of proteins are found in about one fifth of human proteome, and a group of LC-domains form labile cross-β polymers and liquid-like droplets. Polymers and droplets formed from LC-domains are dynamically regulated by posttranslational modifications and molecular chaperones including nuclear transport receptors. Repeat expansion in the first intron of a gene designated C9orf72, which is the most prevalent form of familial amyotrophic lateral sclerosis (ALS), causes nucleocytoplasmic transport deficit, however, the detailed mechanism remains unsolved. Here we show that the proline:arginine (PR) poly-dipeptides encoded by the C9orf72 repeat expansion bound nuclear transport receptor Kapβ2 through its nuclear localization signal (NLS) recognition motif, and inhibited the ability of Kapβ2 to melt fused in sarcoma (FUS) droplets by competing interaction with FUS. The findings in this study offer mechanistic insights as to how the C9orf72 repeat expansion disables nucleocytoplasmic transport and causes neurodegenerative diseases.

scholarly journals The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Nature ◽  
2015 ◽  
Vol 525 (7567) ◽  
pp. 56-61 ◽  
Author(s):  
Ke Zhang ◽  
Christopher J. Donnelly ◽  
Aaron R. Haeusler ◽  
Jonathan C. Grima ◽  
James B. Machamer ◽  
...  
Keyword(s):  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion

scholarly journals Interactions between Mad1p and the Nuclear Transport Machinery in the YeastSaccharomyces cerevisiae

2005 ◽  
Vol 16 (9) ◽  
pp. 4362-4374 ◽  
Author(s):  
Robert J. Scott ◽  
C. Patrick Lusk ◽  
David J. Dilworth ◽  
John D. Aitchison ◽  
Richard W. Wozniak
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Nuclear Transport ◽  
Coiled Coil ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Docking Site ◽  
Cellular Functions ◽  
Yeast Saccharomyces Cerevisiae ◽  
C Terminus ◽  
Localization Signal

In addition to its role in nucleocytoplasmic transport, the nuclear pore complex (NPC) acts as a docking site for proteins whose apparent primary cellular functions are unrelated to nuclear transport, including Mad1p and Mad2p, two proteins of the spindle assembly checkpoint (SAC) machinery. To understand this relationship, we have mapped domains of yeast Saccharomyces cerevisiae Mad1p that interact with the nuclear transport machinery, including further defining its interactions with the NPC. We showed that a Kap95p/Kap60p-dependent nuclear localization signal, positioned in the C-terminal third of Mad1p, is required for its efficient targeting to the NPC. At the NPC, Mad1p interacts with Nup53p and a presumed Nup60p/Mlp1p/Mlp2p complex through two coiled coil regions within its N terminus. When the SAC is activated, a portion of Mad1p is recruited to kinetochores through an interaction that is mediated by the C-terminal region of Mad1p and requires energy. We showed using photobleaching analysis that in nocodazole-arrested cells Mad1p rapidly cycles between the Mlp proteins and kinetochores. Our further analysis also showed that only the C terminus of Mad1p is required for SAC function and that the NPC, through Nup53p, may act to regulate the duration of the SAC response.

scholarly journals The Role of Protein Disorder in Nuclear Transport and in Its Subversion by Viruses

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2654
Author(s):  
Jacinta M. Wubben ◽  
Sarah C. Atkinson ◽  
Natalie A. Borg
Keyword(s):  
Nuclear Transport ◽  
Intrinsic Disorder ◽  
Viral Proteins ◽  
Nucleocytoplasmic Transport ◽  
Transport Barrier ◽  
Inherent Feature ◽  
Viral Infectious Disease ◽  
Transport Receptors ◽  
Protein Intrinsic Disorder ◽  
Import And Export

The transport of host proteins into and out of the nucleus is key to host function. However, nuclear transport is restricted by nuclear pores that perforate the nuclear envelope. Protein intrinsic disorder is an inherent feature of this selective transport barrier and is also a feature of the nuclear transport receptors that facilitate the active nuclear transport of cargo, and the nuclear transport signals on the cargo itself. Furthermore, intrinsic disorder is an inherent feature of viral proteins and viral strategies to disrupt host nucleocytoplasmic transport to benefit their replication. In this review, we highlight the role that intrinsic disorder plays in the nuclear transport of host and viral proteins. We also describe viral subversion mechanisms of the host nuclear transport machinery in which intrinsic disorder is a feature. Finally, we discuss nuclear import and export as therapeutic targets for viral infectious disease.

scholarly journals Scaffold nucleoporins Nup188 and Nup192 share structural and functional properties with nuclear transport receptors

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Kasper R Andersen ◽  
Evgeny Onischenko ◽  
Jeffrey H Tang ◽  
Pravin Kumar ◽  
James Z Chen ◽  
...  
Keyword(s):  
Nuclear Transport ◽  
Evolutionary Relationship ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Rotational Axis ◽  
Nuclear Pore Complexes ◽  
Facilitated Diffusion ◽  
Structural And Functional Properties ◽  
Transport Receptors ◽  
Pore Complexes

Nucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs) embedded in the nuclear envelope. About 30 different proteins (nucleoporins, nups) arrange around a central eightfold rotational axis to build the modular NPC. Nup188 and Nup192 are related and evolutionary conserved, large nucleoporins that are part of the NPC scaffold. Here we determine the structure of Nup188. The protein folds into an extended stack of helices where an N-terminal 130 kDa segment forms an intricate closed ring, while the C-terminal region is a more regular, superhelical structure. Overall, the structure has distant similarity with flexible S-shaped nuclear transport receptors (NTRs). Intriguingly, like NTRs, both Nup188 and Nup192 specifically bind FG-repeats and are able to translocate through NPCs by facilitated diffusion. This blurs the existing dogma of a clear distinction between stationary nups and soluble NTRs and suggests an evolutionary relationship between the NPC and the soluble nuclear transport machinery.

scholarly journals Cargo transport through the nuclear pore complex at a glance

2021 ◽  
Vol 134 (2) ◽  
pp. jcs247874
Author(s):  
Giulia Paci ◽  
Joana Caria ◽  
Edward A. Lemke
Keyword(s):  
Nuclear Pore Complex ◽  
Nuclear Transport ◽  
Cell Cycle Control ◽  
Genetic Material ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Cargo Transport ◽  
Transport Receptors ◽  
Bidirectional Transport ◽  
Transport Of Macromolecules

ABSTRACTBidirectional transport of macromolecules across the nuclear envelope is a hallmark of eukaryotic cells, in which the genetic material is compartmentalized inside the nucleus. The nuclear pore complex (NPC) is the major gateway to the nucleus and it regulates nucleocytoplasmic transport, which is key to processes including transcriptional regulation and cell cycle control. Accordingly, components of the nuclear transport machinery are often found to be dysregulated or hijacked in diseases. In this Cell Science at a Glance article and accompanying poster, we provide an overview of our current understanding of cargo transport through the NPC, from the basic transport signals and machinery to more emerging aspects, all from a ‘cargo perspective’. Among these, we discuss the transport of large cargoes (>15 nm), as well as the roles of different cargo properties to nuclear transport, from size and number of bound nuclear transport receptors (NTRs), to surface and mechanical properties.

scholarly journals SUMO-1 Modification and Its Role in Targeting the Ran GTPase-activating Protein, RanGAP1, to the Nuclear Pore Complex

1998 ◽  
Vol 140 (3) ◽  
pp. 499-509 ◽  
Author(s):  
Michael J. Matunis ◽  
Jian Wu ◽  
Günter Blobel
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Gtpase Activating Protein ◽  
Terminal Domain ◽  
Localization Signal

RanGAP1 is the GTPase-activating protein for Ran, a small ras-like GTPase involved in regulating nucleocytoplasmic transport. In vertebrates, RanGAP1 is present in two forms: one that is cytoplasmic, and another that is concentrated at the cytoplasmic fibers of nuclear pore complexes (NPCs). The NPC-associated form of RanGAP1 is covalently modified by the small ubiquitin-like protein, SUMO-1, and we have recently proposed that SUMO-1 modification functions to target RanGAP1 to the NPC. Here, we identify the domain of RanGAP1 that specifies SUMO-1 modification and demonstrate that mutations in this domain that inhibit modification also inhibit targeting to the NPC. Targeting of a heterologous protein to the NPC depended on determinants specifying SUMO-1 modification and also on additional determinants in the COOH-terminal domain of RanGAP1. SUMO-1 modification and these additional determinants were found to specify interaction between the COOH-terminal domain of RanGAP1 and a region of the nucleoporin, Nup358, between Ran-binding domains three and four. Together, these findings indicate that SUMO-1 modification targets RanGAP1 to the NPC by exposing, or creating, a Nup358 binding site in the COOH-terminal domain of RanGAP1. Surprisingly, the COOH-terminal domain of RanGAP1 was also found to harbor a nuclear localization signal. This nuclear localization signal, and the presence of nine leucine-rich nuclear export signal motifs, suggests that RanGAP1 may shuttle between the nucleus and the cytoplasm.

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