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Nuclear Protein Sorting01:34

Nuclear Protein Sorting

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Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
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Updated: Jul 1, 2025

Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron-like NSC-34 Cells
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C9orf72 polyPR directly binds to various nuclear transport components.

Hamidreza Jafarinia1, Erik van der Giessen1, Patrick R Onck1

  • 1Zernike Institute for Advanced Materials, University of Groningen, Groningen, Netherlands.

Elife
|March 14, 2024
PubMed
Summary

Arginine-rich dipeptide repeat proteins (R-DPRs) disrupt nuclear transport in C9orf72-ALS by binding to key transport proteins. This molecular interaction explains potential defects in nucleocytoplasmic transport (NCT) and C9orf72 toxicity.

Keywords:
ALS/FTDC9orf72importins/exportinsmolecular dynamicsneurosciencenonenuclear pore complexnucleocytoplasmic transportphysics of living systems

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Area of Science:

  • Molecular biology
  • Neuroscience
  • Biophysics

Background:

  • Nucleocytoplasmic transport (NCT) disruption is implicated in neurodegenerative diseases like C9orf72-associated Amyotrophic Lateral Sclerosis (ALS).
  • Arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72, are hypothesized to interfere with NCT by binding to nuclear transport receptors, such as the Kapβ family.
  • The precise molecular mechanisms underlying NCT impairments in R-DPR-expressing cells remain unclear.

Purpose of the Study:

  • To investigate the direct molecular interactions between polyPR, a toxic R-DPR, and various nuclear transport components.
  • To elucidate the binding mechanisms and provide a comprehensive understanding of potential polyPR-mediated defects in nucleocytoplasmic transport (NCT).
  • To explore the role of these interactions in the pathogenesis of C9orf72-related neurodegeneration.

Main Methods:

  • Utilized a coarse-grained molecular dynamics model at amino acid resolution.
  • Simulated the direct interaction between polyPR and multiple nuclear transport factors.
  • Analyzed binding sites and potential interference with transport processes.

Main Results:

  • PolyPR was found to directly bind to Impα isoforms, CAS, and RanGAP.
  • No binding was observed between polyPR and Ran.
  • Longer polyPR chains, at lower salt concentrations, also interacted with RanGEF and NTF2.
  • Analysis revealed potential interference with RanGTP/RanGDP binding, cargo-Impα interactions, and Impα nuclear export.

Conclusions:

  • PolyPR directly interacts with multiple components of the nuclear pore complex (NPC) transport machinery.
  • These interactions can disrupt essential NCT processes, including cargo binding and release, and nuclear export.
  • The findings suggest that direct polyPR interference with NCT is a plausible mechanism contributing to C9orf72 toxicity in neurodegenerative diseases.