Integrative spatiotemporal map of nucleocytoplasmic transport DOI Open Access
Barak Raveh,

Roi Eliasian,

Shaked Rashkovits

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 2, 2024

The Nuclear Pore Complex (NPC) facilitates rapid and selective nucleocytoplasmic transport of molecules as large ribosomal subunits viral capsids. It is not clear how key emergent properties this arise from the system components their interactions. To address question, we constructed an integrative coarse-grained Brownian dynamics model through a single NPC, followed by coupling it with kinetic Ran-dependent in entire cell. microscopic parameters were fitted to reflect experimental data theoretical information regarding transport, without making any assumptions about its properties. resulting reductionist validated reproducing several features used for construction, such morphology central transporter, rates passive facilitated diffusion function size valency, situ radial distributions pre-ribosomal subunits, active suggests that NPC functions essentially virtual gate whose flexible phenylalanine-glycine (FG) repeat proteins raise entropy barrier pore. Importantly, core functionality greatly enhanced design features, including 'fuzzy' transient interactions, multivalency, redundancy copy number FG nucleoporins, exponential kinetics thermodynamics accordance transition state theory, energy-reliant RanGTP concentration gradient. These result robust resilient rate selectivity wide array cargo ranging few kilodaltons megadaltons size. By dissecting these our provides quantitative starting point rationally modulating artificial mimics.

Language: Английский

The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

258
The HIV capsid mimics karyopherin engagement of FG-nucleoporins DOI Creative Commons
Claire F. Dickson, Sophie Hertel, Andrew Tuckwell

et al.

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 24, 2024

Abstract HIV can infect non-dividing cells because the viral capsid overcome selective barrier of nuclear pore complex and deliver genome directly into nucleus 1,2 . Remarkably, intact is more than 1,000 times larger size limit prescribed by diffusion 3 This in central channel composed intrinsically disordered nucleoporin domains enriched phenylalanine–glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins their bound cargoes solubilize this phase to drive nucleocytoplasmic transport 4 By performing an vitro dissection complex, we show that a pocket on surface similarly interacts with motifs from multiple nucleoporins interaction licences capsids penetrate FG-nucleoporin condensates. karyopherin mimicry model addresses key conceptual challenge for role entry offers explanation as how exogenous entity much any known cargo may be able non-destructively breach envelope.

Language: Английский

Citations

59
HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex DOI Creative Commons
Arpa Hudait, Gregory A. Voth

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(4)

Published: Jan. 19, 2024

Nuclear import and uncoating of the viral capsid are critical steps in HIV-1 life cycle that serve to transport release genomic material into nucleus. Viral core involves translocating at nuclear pore complex (NPC). Notably, central channel NPC appears often accommodate allow passage intact capsid, though mechanistic details process remain be fully understood. Here, we investigate molecular interactions operate concert between regulate translocation through channel. To this end, develop a “bottom-up” coarse-grained (CG) model human from recently released cryo-electron tomography structure then construct composite membrane-embedded CG models. We find successful cytoplasmic side is contingent on compatibility morphology dimension proper orientation approach side. The dynamics driven by maximizing contacts phenylalanine-glycine nucleoporins capsid. For docked capsids, structural analysis reveals correlated striated patterns lattice disorder likely related intrinsic elasticity. Uncondensed inside augments overall Our results suggest “elasticity” can also aid adapt stress structurally during translocation.

Language: Английский

Citations

23
Understanding the cell: Future views of structural biology DOI Creative Commons
Martin Beck, Roberto Covino, Inga Hänelt

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(3), P. 545 - 562

Published: Feb. 1, 2024

Determining the structure and mechanisms of all individual functional modules cells at high molecular detail has often been seen as equal to understanding how work. Recent technical advances have led a flush high-resolution structures various macromolecular machines, but despite this wealth detailed information, our cellular function remains incomplete. Here, we discuss present-day limitations structural biology highlight novel technologies that may enable us analyze functions directly inside cells. We predict progression toward cell will involve shift conceptualizing 4D virtual reality using digital twins. These capture segments in highly enriched detail, include dynamic changes, facilitate simulations processes, leading experimentally testable predictions. Transferring biological questions into algorithms learn from existing data explore solutions ultimately unveil

Language: Английский

Citations

23
Passage of the HIV capsid cracks the nuclear pore DOI Creative Commons
Jan Philipp Kreysing, Maziar Heidari, Vojtěch Žíla

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

15
Disordered regions of condensate-promoting proteins have distinct molecular signatures associated with cellular function DOI
Shubham Vashishtha, Benjamin R. Sabari

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168953 - 168953

Published: Jan. 1, 2025

Language: Английский

Citations

3
Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation DOI Creative Commons
Ashish Joshi,

Anuja Walimbe,

Anamika Avni

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 13, 2023

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to be associated with a wide range cellular functions dysfunctions. We dissect critical molecular events an intrinsically disordered prion-like low-complexity domain Fused in Sarcoma by performing single-molecule studies permitting us access the wealth information that is skewed conventional ensemble experiments. Our FRET experiments reveal coexistence two conformationally distinct subpopulations monomeric form. Single-droplet coupled fluorescence correlation spectroscopy, picosecond time-resolved anisotropy, vibrational Raman spectroscopy indicate structural unwinding switches intramolecular interactions into intermolecular contacts allowing formation dynamic network within condensates. A disease-related mutation introduces enhanced plasticity engendering greater interchain can accelerate pathological aggregation. findings provide key mechanistic underpinnings sequence-encoded dynamically-controlled unzipping resulting biological separation.

Language: Английский

Citations

28
Conformational Properties of Polymers at Droplet Interfaces as Model Systems for Disordered Proteins DOI Creative Commons
Jiahui Wang, Dinesh Sundaravadivelu Devarajan, Arash Nikoubashman

et al.

ACS Macro Letters, Journal Year: 2023, Volume and Issue: 12(11), P. 1472 - 1478

Published: Oct. 19, 2023

Polymer models serve as useful tools for studying the formation and physical properties of biomolecular condensates. In recent years, interface dividing dense dilute phases condensates has been discovered to be closely related their functionality, but conformational preferences constituent proteins remain unclear. To elucidate this, we perform molecular simulations a droplet formed by phase separation homopolymers surrogate model prion-like low-complexity domains. By systematically analyzing polymer conformations at different locations in droplet, find that chains become compact compared with interior. Further, segmental analysis revealed end sections are enriched maximize entropy more expanded than middle chains. We majority chain segments lie tangential surface, only ends tend align perpendicular interface. These trends also hold natural FUS LC LAF-1 RGG, which exhibit Our findings provide important insights into interfacial highlight value using simple physics understand underlying mechanisms.

Language: Английский

Citations

25
Cracking the Code: Reprogramming the Genetic Script in Prokaryotes and Eukaryotes to Harness the Power of Noncanonical Amino Acids DOI

Cosimo Jann,

Sabrina Giofrè,

Rajanya Bhattacharjee

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(18), P. 10281 - 10362

Published: Aug. 9, 2024

Over 500 natural and synthetic amino acids have been genetically encoded in the last two decades. Incorporating these noncanonical into proteins enables many powerful applications, ranging from basic research to biotechnology, materials science, medicine. However, major challenges remain unleash full potential of genetic code expansion across disciplines. Here, we provide an overview diverse methodologies systems their final applications prokaryotes eukaryotes, represented by

Language: Английский

Citations

18
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD DOI Creative Commons
Bilal Khalil,

Miriam Linsenmeier,

Courtney L. Smith

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 22, 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that characterized by the cytoplasmic mislocalization aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), other nuclear RBPs detergent-insoluble aggregates cytoplasm degenerating neurons ALS/FTD is connected to pore dysfunction defects nucleocytoplasmic transport machinery. Recent advances suggest beyond their canonical role import protein cargoes, nuclear-import receptors (NIRs) can prevent reverse TDP-43, FUS, related restore localization function. Here, we showcase NIR family how they recognize cargo, drive import, chaperone linked ALS/FTD. We also discuss promise enhancing levels developing potentiated variants as therapeutic strategies for proteinopathies.

Language: Английский

Citations

16