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#nuclear transport

12 public questions tagged with this topic.

Cell Organelles

The primary function of nuclear pores is:

Nuclear envelope is perforated by two thousand to four thousand pores per mammalian nucleus, each one hundred twenty nanometers diameter channel composed of nucleoporins forming selective barrier separating nuclear and cytoplasmic compartments. Central channel filled with phenylalanine-glycine repeat containing disordered domains forms hydrogel allowing passive diffusion of ions and molecules under about forty kDa, but macromolecules bearing nuclear localization signals require binding to importin alpha-beta heterodimers and transit via transient interaction with FG repeats powered by Ran-GTP

Ref: Wente Genes Dev; NPC 120nm FG nucleoporins regulated transport Ran-GTP importin exportin.

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Protein Sorting and Trafficking

Which enzyme is required for GTP hydrolysis in nuclear transport?

Termination of Ran-mediated signaling requires stimulation of weak intrinsic GTPase activity by GTPase activating proteins that insert catalytic arginine finger into nucleotide binding site stabilizing transition state for hydrolysis. Cytoplasmic RanGAP1 SUMOylated and anchored to Nup358/RanBP2 at cytoplasmic filaments of pore, together with soluble co-activator RanBP1 that holds Ran in optimal conformation presenting switch regions, accelerates hydrolysis of Ran-GTP to Ran-GDP more than hundredfold, releasing inorganic phosphate. This reaction disassembles export complexes in cytosol, prevent

Ref: Bischoff et al., PNAS 91: 1994, RanGAP1 Stimulates Ran GTP Hydrolysis.

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Protein Sorting and Trafficking

What role does NTF2 play in nuclear transport?

Maintenance of steep Ran gradient requires continuous recycling of Ran between compartments after hydrolysis. Ran-GDP formed in cytoplasm diffuses poorly across pore and requires facilitated import. Nuclear transport factor 2, small 14 kilodalton homodimer forming beta-sandwich barrel with hydrophobic cavity, specifically binds Ran-GDP conformation with high affinity but excludes Ran-GTP because switch I and switch II regions adopt different positions blocking NTF2 interaction. NTF2-Ran-GDP complex interacts transiently with FG repeats of central nucleoporins Nup62, Nup58 and Nup54 via surface

Ref: Stewart M et al., J Cell Biol 147: 1999, NTF2 Imports Ran-GDP into Nucleus.

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Protein Sorting and Trafficking

The major energy source for nuclear transport is:

Energy input driving selective accumulation of proteins inside nucleus does not come from kinesin ATP hydrolysis used for microtubule transport or proton motive force powering mitochondrial import, but from compartmentalized GTP turnover of Ran. RCC1 guanine exchange factor bound to nucleosomes continuously recharges Ran-GDP to Ran-GTP using nuclear GTP pool, while cytoplasmic RanGAP1 SUMOylated and anchored to RanBP2/Nup358 plus co-activator RanBP1 hydrolyze GTP outside. Each import cycle consumes one GTP upon export complex disassembly in cytosol, and each export cycle consumes GTP as Ran-GT

Ref: NCBI Bookshelf, Molecular Biology of the Cell, Section: GTP Hydrolysis by Ran as Energy Source.

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Protein Sorting and Trafficking

Which of the following proteins is not required for nuclear export of mRNA?

Nuclear export of mature messenger ribonucleoproteins employs dedicated adaptors that recognize RNA processing marks rather than leucine-rich export signals. After splicing, exon junction complex and cap binding complex recruit TREX components including THO complex, UAP56 helicase and Aly/REF adaptor coating 5' region of transcript and providing platform for NXF1-NXT1 heterodimer, called TAP-p15 in metazoans, that binds via arginine-rich domains and directly engages FG nucleoporins through its NTF2-like and UBA domains for translocation. On cytoplasmic face, DDX19/Dbp5 helicase anchored by Nup

Ref: Köhler & Hurt, Nature Rev Mol Cell Biol 8: 2007, NXF1-NXT1 and Dbp5 in mRNA Export, Ran Independence.

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Protein Sorting and Trafficking

Which of the following processes is not directly dependent on Ran-GTP?

Most nuclear import of NLS proteins using importin-alpha-beta heterodimer and export of NES proteins via CRM1 strictly consume Ran-GTP cycles, with RCC1 generating Ran-GTP inside nucleus and RanGAP1 hydrolyzing outside. Each cycle consumes one GTP and relies on NTF2 recycling of Ran-GDP. Messenger RNA departure follows divergent energetic logic. Bulk poly(A) mRNA transcribed, spliced and polyadenylated recruits TREX complex and adaptor Aly/REF that loads heterodimer NXF1-NXT1 which binds FG repeats directly without Ran. At cytoplasmic filaments of pore, DEAD-box helicase Dbp5/DDX19 activated b

Ref: Stewart M, Nature Rev Mol Cell Biol 8: 2007, Ran-Dependent Protein Transport versus Ran-Independent mRNA Export.

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Protein Sorting and Trafficking

Which protein is responsible for releasing cargo from the importin receptor in the nucleus?

Efficient nuclear import demands timely liberation of cargo after arrival inside nucleoplasm so it can engage chromatin, transcription machinery or splicing. Importin-beta-cargo interaction stable in cytoplasm where Ran-GTP scarce becomes unstable upon encountering high nuclear Ran-GTP concentration. Ran-GTP docks onto N-terminal arch of importin-beta composed of HEAT repeats, inducing large allosteric opening that widens superhelical curvature and disrupts binding interface for importin-alpha IBB domain and for FG nucleoporins. Importin-alpha affinity for basic NLS drops, cargo released aided

Ref: Vetter et al., Nature 392: 1998, RanGTP Dissociates Import Complexes in Nucleus.

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Protein Sorting and Trafficking

What ensures directionality in nuclear protein transport?

Unidirectional accumulation of proteins against concentration gradients through nuclear pores cannot arise from gate selectivity alone because FG nucleoporin mesh permits diffusion in both directions. Direction emerges from asymmetric distribution of Ran regulators generating chemical potential. Nuclear RCC1 bound to chromatin continuously exchanges GDP for GTP using nuclear GTP pool, while cytoplasmic RanGAP1 SUMOylated and tethered to RanBP2/Nup358 plus soluble RanBP1 hydrolyzes GTP outside, creating gradient high inside low outside, more than hundred-fold difference. Importins bind NLS carg

Ref: Nature Reviews Mol Cell Biol 20: 2019, Ran GTPase Gradient as Directionality Determinant in Nuclear Transport.

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Protein Sorting and Trafficking

Which GTPase is specifically involved in nuclear transport?

Ran is small 25 kilodalton Ras-family GTPase that specializes in marking nuclear versus cytoplasmic compartments, unlike Rab, Rho and Ras which control vesicle docking, actin remodeling and MAP kinase signaling elsewhere. Its nucleotide state differs across envelope because regulators are spatially segregated: RCC1 guanine nucleotide exchange factor bound to histones H2A-H2B inside nucleus generates high Ran-GTP, while RanGAP1 SUMOylated and anchored to RanBP2/Nup358 at cytoplasmic filaments together with RanBP1 accelerate GTP hydrolysis outside producing Ran-GDP. This partitioning creates ste

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Chapter 12: Ran GTPase Gradient, RCC1 and RanGAP.

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Protein Sorting and Trafficking

Which of the following is NOT involved in Ran-independent nuclear export of mRNA?

Export of bulk messenger ribonucleoproteins uses machinery fundamentally separate from Ran-dependent protein and small RNA transport. After capping, splicing and polyadenylation, nascent mRNPs acquire TREX complex including THO subcomplex, DEAD-box helicase UAP56 and adaptors Aly/REF and Thp1 that coat transcript and provide binding platform for export receptor. Heterodimer NXF1-NXT1, called TAP-p15 in metazoans, directly contacts FG repeats of central nucleoporins via its NTF2-like and UBA domains to drive translocation without karyopherins or Ran gradient. Directionality and release do not i

Ref: Stewart M, Science 318: 2007, Nuclear Export of mRNA via NXF1-NXT1 and Dbp5 Helicase.

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Protein Sorting and Trafficking

Ran-GTP is primarily involved in:

Directionality of nucleocytoplasmic transport relies on asymmetric distribution of small GTPase Ran nucleotide states forming gradient across nuclear envelope. Regulator RCC1 RanGEF bound to chromatin generates high Ran-GTP concentration inside nucleus through exchange of GDP for GTP, while cytoplasmic filaments of nuclear pore complex associated with RanGAP and RanBP1 stimulate GTP hydrolysis to Ran-GDP in cytosol, depleting Ran-GTP outside. Importin alpha/beta-cargo complexes formed in cytoplasm traverse pore via interactions with FG nucleoporins, encountering Ran-GTP in nucleus which binds

Ref: Gorlich & Kutay, Annu Rev Cell Dev Biol 1999, Ran Gradient. Alberts 7th ed., Chapter 12, Transport.

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What is the function of the nuclear pore complex (NPC)?

Barrier between genome and cytoplasm is perforated by nuclear pore complexes large supramolecular structures of approximately 125 megadaltons composed of about 30 distinct nucleoporins present in multiple copies arranged with eightfold rotational symmetry spanning double nuclear membranes. Outer scaffold comprises Y-shaped Nup107-160 subcomplex forming two concentric rings, inner ring composed of Nup205, Nup188, Nup155 anchoring central channel filled with disordered FG repeats rich in phenylalanine-glycine motifs that form selective phase limiting diffusion. Molecules smaller than 40 kilodalt

Ref: Hurt & Beck, Cell 2015, Nuclear Pore Architecture. Alberts 7th ed., Chapter 12, NPC Function.

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