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PreprintCited by 0Amyotrophic Lateral Sclerosis ResearchNuclear Structure and FunctionGenetic Neurodegenerative Diseases

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C9orf72 polyPR directly binds to various nuclear transport components

Open access
Jafarinia, Hamidreza, Van der Giessen, Erik, Onck, Patrick R.·2023·eLife
DOI 10.7554/elife.89694.2

Preprint — published as 10.7554/elife.89694.3 · Paper page

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Abstract

Abstract The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Beside Kapβs, several other types of transport components have been linked to NCT impairments in R-DPRs expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino-acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.

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Metadata

Authors
Jafarinia, H., Van der Giessen, E., & Onck, P. R.
Affiliations
  • University of Groningen (NL)
  • Zernike Institute for Advanced Materials, University of Groningen
Corresponding author
Onck, Patrick R.
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-12-27
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.89694.2
OpenAlex
W4390267702
Cited by
0
References
3
Type
posted content
Language
en
Open access
Licence
Locations
eLife (acceptedVersion, cc-by)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Building Blocks of Life)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
C9orf72, polyarginine, dipeptide repeat proteins, nuclear transport, nuclear pore complex, nuclear transport receptors, RanGAP, NTF2, CAS, nuclear localization signal, protein-protein binding, coarse-grained molecular dynamics

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