Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles

Schmidt, Hermann Broder; Görlich, Dirk

doi:10.1016/j.tibs.2015.11.001

Cited by 386 publications

(370 citation statements)

References 131 publications

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“…These flexible LCDs project into the central channel, where they interact and assemble into a gellike structure that defines the permeability barrier of the pore (19). McKnight and coworkers examined FG domains of two Nups (Nup54 and Nup98) by transmission electron microscopy and X-ray diffraction, revealing assembly into amyloid-like fibrils composed of a cross-beta structure, similar to assemblies observed in previous studies (20) of related FG Nups.…”

supporting

confidence: 53%

A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Taylor

2017

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

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supporting

confidence: 53%

A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Taylor

2017

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

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“…These three rings anchor additional, non-scaffolding Nups that comprise the central channel, cytoplasmic filaments and nuclear basket. Key among the non-scaffolding Nups is a subset of proteins featuring unfolded phenylalanine–glycine (FG)-repeat domains, which are the primary determinants of the permeability and selectivity properties of the NPC (Schmidt and Gorlich, 2016). These same Nups also facilitate NPC biogenesis and stabilize pore structure (Onischenko et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells

et al. 2018

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Summary Nup133 belongs to the Y-complex, a key component of the nuclear pore complex (NPC) scaffold. Studies on a null mutation in mice previously revealed that Nup133 is essential for embryonic development but not for mouse embryonic stem cell (mESC) proliferation. Using single pore detection and average NE-fluorescence intensity, we find that Nup133 is dispensable for interphase and postmitotic NPC scaffold assembly in pluripotent mESCs. However, loss of Nup133 specifically perturbs the formation of the nuclear basket as manifested by the absence of Tpr in about half of the NPCs combined with altered dynamics of Nup153. We further demonstrate that its central domain mediates Nup133's role in assembling Tpr and Nup153 into a properly configured nuclear basket. Our findings thus revisit the role of the Y-complex in pore biogenesis and provide insights into the interplay between NPC scaffold architecture, nuclear basket assembly and the generation of heterogeneity among NPCs.

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“…Intracellular LLPS and the resulting functional membrane‐less organelles, which biophysically can be described as gels or polyelectrolyte brushes, are emerging concepts in cell biology, which are now implicated in manifold cellular functions and applications (Li et al , 2012; Aumiller et al , 2014; Elbaum‐Garfinkle et al , 2015; Jiang et al , 2015; Aguzzi & Altmeyer, 2016; Mitrea et al , 2016; Schmidt & Görlich, 2016; Schmidt & Rohatgi, 2016). For research in neurodegenerative diseases, in particular, the function and misfunction of LLPS by involved proteins—such as tau, FUS, TDP43, hnRNPA1, C9orf72 dipeptide repeats—introduces a novel exciting concept that may provide a common underlying mechanism in these diseases.…”

Section: Discussionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles

Cited by 386 publications

References 131 publications

A PR plug for the nuclear pore in amyotrophic lateral sclerosis

A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells

Tau protein liquid–liquid phase separation can initiate tau aggregation

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