scholarly journals Converging on the function of intrinsically disordered nucleoporins in the nuclear pore complex

2010 ◽  
Vol 391 (7) ◽  
Author(s):  
Orit Peleg ◽  
Roderick Y.H. Lim
Keyword(s):  
Nuclear Pore Complex ◽  
Intrinsically Disordered Proteins ◽  
Molecular Transport ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Biological Mechanisms ◽  
Intrinsically Disordered ◽  
Polymeric Chains ◽  
Insight Into

Abstract Several biological mechanisms involve proteins or proteinaceous components that are intrinsically disordered. A case in point pertains to the nuclear pore complex (NPC), which regulates molecular transport between the nucleus and the cytoplasm. NPC functionality is dependent on unfolded domains rich in Phe-Gly (FG) repeats (i.e., FG-domains) that collectively act to promote or hinder cargo translocation. To a large extent, our understanding of FG-domain behavior is limited to in vitro investigations given the difficulty to resolve them directly in the NPC. Nevertheless, recent findings indicate a collective convergence towards rationalizing FG-domain function. This review aims to glean further insight into this fascinating problem by taking an objective look at the boundary conditions and contextual details underpinning FG-domain behavior in the NPC. Here, we treat the FG-domains as being commensurate with polymeric chains to address ambiguities such as for instance, how FG-domains tethered to the central channel of the NPC would behave differently as compared with their free-floating counterparts in solution. By bringing such fundamental questions to the fore, this review seeks to illuminate the importance of how such parameters can hold influence over the structure-function relation of intrinsically disordered proteins in the NPC and beyond.

scholarly journals Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrei Vovk ◽  
Chad Gu ◽  
Michael G Opferman ◽  
Larisa E Kapinos ◽  
Roderick YH Lim ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Intrinsically Disordered Proteins ◽  
Nucleocytoplasmic Transport ◽  
Transport Proteins ◽  
Disordered Proteins ◽  
Biophysical Model ◽  
Nuclear Pore ◽  
Intrinsically Disordered

Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function.

scholarly journals A Study of Intrinsically Disordered Proteins from Nuclear Pore Complex

2013 ◽  
Vol 104 (2) ◽  
pp. 55a-56a
Author(s):  
Jianhui Tian ◽  
Anton Zilman ◽  
Sandrasegaram Gnanakaran
Keyword(s):  
Nuclear Pore Complex ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Intrinsically Disordered

scholarly journals Physical modelling of multivalent interactions in the nuclear pore complex

2020 ◽  
Author(s):  
Luke K. Davis ◽  
Anđela Šarić ◽  
Bart W. Hoogenboom ◽  
Anton Zilman
Keyword(s):  
Experimental Data ◽  
Single Molecule ◽  
Nuclear Pore Complex ◽  
Intrinsically Disordered Proteins ◽  
Binding Kinetics ◽  
Disordered Proteins ◽  
Minor Role ◽  
Nuclear Pore ◽  
Minimal Models ◽  
Intrinsically Disordered

In the nuclear pore complex (NPC), intrinsically disordered proteins (FG Nups) along with their interactions with more globular proteins called nuclear transport receptors (NTRs) are vital to the selectivity of transport into and out of the cell nucleus. While such interactions can be modelled at different levels of coarse graining, in-vitro experimental data have been quantitatively described by minimal models that describe FG Nups as cohesive homogeneous polymers and NTRs as uniformly cohesive spheres, where the heterogeneous effects have been smeared out. By definition, these minimal models do not account for the explicit heterogeneities in FG Nup sequences, essentially a string of cohesive and non-cohesive polymer units, and at the NTR surface. Here, we develop computational and analytical models that do take into account such heterogeneity at a level of minimal complexity, and compare them to experimental data on single-molecule interactions between FG Nups and NTRs. Overall, we find that the heterogeneous nature of FG Nups and NTRs plays a minor role for their equilibrium binding properties, but is of significance when it comes to (un)binding kinetics. Using our models, we predict how binding equilibria and kinetics depend on the distribution of cohesive blocks in the FG Nup sequences and of the binding pockets at the NTR surface, with multivalency playing a key role. Finally, we observe that single-molecule binding kinetics has a rather minor influence on the diffusion of NTRs in polymer melts consisting of FG-Nup-like sequences.

scholarly journals Intrinsically Disordered Proteins: Gatekeepers of the Nuclear Pore Complex

2016 ◽  
Vol 110 (3) ◽  
pp. 358a
Author(s):  
Ali Ghavami ◽  
Liesbeth M. Veenhoff ◽  
Erik Van der Giessen ◽  
Patrick R. Onck
Keyword(s):  
Nuclear Pore Complex ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Intrinsically Disordered

scholarly journals DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Philip Ketterer ◽  
Adithya N. Ananth ◽  
Diederik S. Laman Trip ◽  
Ankur Mishra ◽  
Eva Bertosin ◽  
...  
Keyword(s):  
Nuclear Pore Complex ◽  
Intrinsically Disordered Proteins ◽  
Dna Origami ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Intrinsically Disordered

scholarly journals The molecular chaperone DNAJB6 provides surveillance of FG-Nups and is required for interphase nuclear pore complex biogenesis

2021 ◽  
Author(s):  
E. F. Elsiena Kuiper ◽  
Paola Gallardo ◽  
Tessa Bergsma ◽  
Muriel Mari ◽  
Maiara Kolbe Musskopf ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Permeability Barrier ◽  
Nuclear Pore Complexes ◽  
Annulate Lamellae ◽  
Intrinsically Disordered ◽  
Pore Complexes

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage/crossing of biomolecules. The FG-Nups are intrinsically disordered and prone to liquid-liquid phase separate and aggregate when isolated. It has remained largely unclear how FG-Nups are protected from making inappropriate interactions during NPC biogenesis. We found that DNAJB6, a molecular chaperone of the heat shock protein network, formed foci next to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Reversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and they could be identified as herniations at the nuclear envelope (NE). Immunoelectron tomography showed that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Interestingly, loss of DNAJB6 results in annulate lamellae, which are structures containing partly assembled NPCs associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG-region of several FG-Nups in cells and in vitro. Together, our data show that DNAJB6 provides quality control during NPC biogenesis and is the first molecular chaperone that is involved in the surveillance of native intrinsically disordered proteins, including FG-Nups.

scholarly journals Baicalein inhibits heparin-induced Tau aggregation by initializing non-toxic Tau oligomer formation

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shweta Kishor Sonawane ◽  
Vladimir N. Uversky ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Senile Plaques ◽  
Neuroblastoma Cells ◽  
Memory Loss ◽  
Disordered Proteins ◽  
Protein Accumulation ◽  
Scutellaria Baicalensis Georgi ◽  
Intrinsically Disordered ◽  
Tau Aggregation

Abstract Background Amyloid aggregate deposition is the key feature of Alzheimer’s disease. The proteinaceous aggregates found in the afflicted brain are the intra-neuronal neurofibrillary tangles formed by the microtubule-associated protein Tau and extracellular deposits, senile plaques, of amyloid beta (Aβ) peptide proteolytically derived from the amyloid precursor protein. Accumulation of these aggregates has manifestations in the later stages of the disease, such as memory loss and cognitive inabilities originating from the neuronal dysfunction, neurodegeneration, and brain atrophy. Treatment of this disease at the late stages is difficult, and many clinical trials have failed. Hence, the goal is to find means capable of preventing the aggregation of these intrinsically disordered proteins by inhibiting the early stages of their pathological transformations. Polyphenols are known to be neuroprotective agents with the noticeable potential against many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Prion diseases. Methods We analyzed the capability of Baicalein to inhibit aggregation of human Tau protein by a multifactorial analysis that included several biophysical and biochemical techniques. Results The potency of Baicalein, a polyphenol from the Scutellaria baicalensis Georgi, against in vitro Tau aggregation and PHF dissolution has been screened and validated. ThS fluorescence assay revealed the potent inhibitory activity of Baicalein, whereas ANS revealed its mechanism of Tau inhibition viz. by oligomer capture and dissociation. In addition, Baicalein dissolved the preformed mature fibrils of Tau thereby possessing a dual target action. Tau oligomers formed by Baicalein were non-toxic to neuronal cells, highlighting its role as a potent molecule to be screened against AD. Conclusion In conclusion, Baicalein inhibits aggregation of hTau40 by enhancing the formation of SDS-stable oligomers and preventing fibril formation. Baicalein-induced oligomers do not affect the viability of the neuroblastoma cells. Therefore, Baicalein can be considered as a lead molecule against Tau pathology in AD.

scholarly journals The Mysterious Unfoldome: Structureless, Underappreciated, Yet Vital Part of Any Given Proteome

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Biologically Active ◽  
Disordered Proteins ◽  
Unfolded Proteins ◽  
Intrinsically Disordered ◽  
Proteome Level ◽  
Natively Unfolded ◽  
Natively Unfolded Proteins

Contrarily to the general believe, many biologically active proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. These intrinsically disordered proteins (IDPs) are highly abundant in nature and many of them are associated with various human diseases. The functional repertoire of IDPs complements the functions of ordered proteins. Since IDPs constitute a significant portion of any given proteome, they can be combined in an unfoldome; which is a portion of the proteome including all IDPs (also known as natively unfolded proteins, therefore, unfoldome), and describing their functions, structures, interactions, evolution, and so forth. Amino acid sequence and compositions of IDPs are very different from those of ordered proteins, making possible reliable identification of IDPs at the proteome level by various computational means. Furthermore, IDPs possess a number of unique structural properties and are characterized by a peculiar conformational behavior, including their high stability against low pH and high temperature and their structural indifference toward the unfolding by strong denaturants. These peculiarities were shown to be useful for elaboration of the experimental techniques for the large-scale identification of IDPs in various organisms. Some of the computational and experimental tools for the unfoldome discovery are discussed in this review.

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