Conformational dynamics of the nuclear pore complex central channel

Biochemical Society Transactions, Год журнала: 2025, Номер 53(01)

Опубликована: Фев. 7, 2025

The nuclear pore complex (NPC) is a vital regulator of molecular transport between the nucleus and cytoplasm in eukaryotic cells. At heart NPC’s function are intrinsically disordered phenylalanineglycine-rich nucleoporins (FG-Nups), which form dynamic permeability barrier within central channel. This nature facilitates efficient nucleocytoplasmic but also poses significant challenges to its characterization, especially nano-confined environment NPC. Recent advances experimental techniques, such as cryo-electron microscopy, atomic force fluorescence magnetic resonance, along with computational modeling, have illuminated conformational flexibility FG-Nups, underpins their functional versatility. review synthesizes these advancements, emphasizing how disruptions FG-Nup behavior—caused by mutations or pathological interactions—contribute diseases neurodegenerative disorders, aging-related decline, viral infections. Despite progress, persist deciphering dynamics crowded cellular environment, under conditions. Addressing gaps critical for advancing therapeutic strategies targeting NPC dysfunction disease progression.

Язык: Английский

Intrinsic stiffness and Θ-solvent regime in intrinsically disordered proteins: Implications for liquid-liquid phase separation

PNAS Nexus, Год журнала: 2025, Номер 4(2)

Опубликована: Фев. 1, 2025

Liquid-liquid phase separation (LLPS) exhibited by intrinsically disordered proteins (IDPs) depends on the solvation state around Θ-regime, which separates good from poor solvent. Experimentally, Θ-solvent regime of finite length (N) IDPs, as probed small angle X-ray scattering (SAXS) and single molecular fluorescence resonance energy transfer (smFRET), is in disagreement. Using computer simulations a coarse-grained IDP model, we address effect chain Θ-regime IDPs with polar side chains (polyglutamine) hydrophobic (polyleucine) subject to varying concentrations cosolvents [C] , urea (denaturant) or trimethylamine N-oxide (protective osmolyte) water. Due their intrinsic stiffness, these are always expanded short-length scales, independent solvent quality. As result, for short sequences ( ≈10 25 residues), propensity exhibit LLPS cannot be inferred single-chain properties. Further, finite-size cosolvent concentration attain [CΘ] ) extracted structure factor emulating SAXS pair distances mimicking smFRET differs. They converge same only at large N, indicating that size corrections vary different We show radius gyration Rg satisfies scaling relation Rg2=Nf(cN) can exploited accurately extract c=([C]/[CΘ]-1) ). demonstrate importance aspects originating stiffness thermal blob analyzing properties identify regime.

Язык: Английский