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Cited by 2Amyotrophic Lateral Sclerosis ResearchNuclear Structure and FunctionGenetic Neurodegenerative Diseases

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C9orf72 polyPR directly binds to various nuclear transport components

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Jafarinia, Hamidreza, van der Giessen, Erik, Onck, Patrick R·2024·eLife
DOI 10.7554/elife.89694.3

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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. Besides Kapβs, several other types of transport components have been linked to NCT impairments in R-DPR-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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Research works printed but not linked: 52

  1. Ananth, 2018, Spatial structure of disordered proteins dictates conductance and selectivity in nuclear pore complex mimics, eLife, 7, 10.7554/eLife.31510 · DOI
  2. Balendra, 2018, C9orf72-mediated ALS and FTD: multiple pathways to disease, Nature Reviews. Neurology, 14, 544, 10.1038/s41582-018-0047-2 · DOI · Paper page
  3. Bennion Callister, 2016, Modelling C9orf72 dipeptide repeat proteins of a physiologically relevant size, Human Molecular Genetics, 25, 5069, 10.1093/hmg/ddw327 · DOI
  4. Boeynaems, 2016, Inside out: the role of nucleocytoplasmic transport in ALS and FTLD, Acta Neuropathologica, 132, 159, 10.1007/s00401-016-1586-5 · DOI
  5. Bullock, 1996, The 1.6 angstroms resolution crystal structure of nuclear transport factor 2 (NTF2), Journal of Molecular Biology, 260, 422, 10.1006/jmbi.1996.0411 · DOI
  6. Cook, 2005, The structure of the nuclear export receptor Cse1 in its cytosolic state reveals a closed conformation incompatible with cargo binding, Molecular Cell, 18, 355, 10.1016/j.molcel.2005.03.021 · DOI
  7. DeJesus-Hernandez, 2011, Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS, Neuron, 72, 245, 10.1016/j.neuron.2011.09.011 · DOI · Paper page
  8. Dekker, 2022, Liquid-Liquid Phase Separation of Intrinsically Disordered FG-Nups Is Driven by Highly-Dynamic Hydrophobic FG-Motifs, 10.1101/2022.09.20.508740 · DOI
  9. Fragasso, 2021, A designer FG-Nup that reconstitutes the selective transport barrier of the nuclear pore complex, Nature Communications, 12, 10.1038/s41467-021-22293-y · DOI
  10. Freibaum, 2015, GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport, Nature, 525, 129, 10.1038/nature14974 · DOI · Paper page
  11. Ghavami, 2013, Coarse-grained potentials for local interactions in unfolded proteins, Journal of Chemical Theory and Computation, 9, 432, 10.1021/ct300684j · DOI
  12. Ghavami, 2014, Probing the disordered domain of the nuclear pore complex through coarse-grained molecular dynamics simulations, Biophysical Journal, 107, 1393, 10.1016/j.bpj.2014.07.060 · DOI
  13. Ghavami, 2016, Energetics of transport through the nuclear pore complex, PLOS ONE, 11, 10.1371/journal.pone.0148876 · DOI
  14. Görlich, 2003, Characterization of Ran-driven cargo transport and the RanGTPase system by kinetic measurements and computer simulation, The EMBO Journal, 22, 1088, 10.1093/emboj/cdg113 · DOI
  15. Haberland, 1997, The acidic C-terminal domain of rna1p is required for the binding of Ran.GTP and for RanGAP activity, The Journal of Biological Chemistry, 272, 24717, 10.1074/jbc.272.39.24717 · DOI
  16. Hayes, 2020, C9orf72 arginine-rich dipeptide repeat proteins disrupt karyopherin-mediated nuclear import, eLife, 9, 10.7554/eLife.51685 · DOI
  17. Higurashi, 2009, PiSite: a database of protein interaction sites using multiple binding states in the PDB, Nucleic Acids Research, 37, D360, 10.1093/nar/gkn659 · DOI
  18. Hillig, 1999, The crystal structure of rna1p: a new fold for a GTPase-activating protein, Molecular Cell, 3, 781, 10.1016/s1097-2765(01)80010-1 · DOI
  19. Hutten, 2020, Nuclear import receptors directly bind to arginine-rich dipeptide repeat proteins and suppress their pathological interactions, Cell Reports, 33, 10.1016/j.celrep.2020.108538 · DOI
  20. Jafarinia, 2020, Phase Separation of Toxic Dipeptide Repeat Proteins Related to C9orf72 ALS/FTD, Biophysical Journal, 119, 843, 10.1016/j.bpj.2020.07.005 · DOI
  21. Jafarinia, 2022, Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors, Scientific Reports, 12, 10.1038/s41598-022-25732-y · DOI
  22. Jovičić, 2015, Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS, Nature Neuroscience, 18, 1226, 10.1038/nn.4085 · DOI · Paper page
  23. Jovičić, 2016, Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia, Journal of Neurochemistry, 138 Suppl 1, 134, 10.1111/jnc.13642 · DOI
  24. Kalita, 2021, On the asymmetric partitioning of nucleocytoplasmic transport - recent insights and open questions, Journal of Cell Science, 134, 10.1242/jcs.240382 · DOI
  25. Kim, 2017, Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases, Neuron, 96, 285, 10.1016/j.neuron.2017.07.029 · DOI
  26. Kramer, 2018, CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity, Nature Genetics, 50, 603, 10.1038/s41588-018-0070-7 · DOI · Paper page
  27. Kwon, 2014, Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells, Science, 345, 1139, 10.1126/science.1254917 · DOI
  28. Lee, 2016, C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles, Cell, 167, 774, 10.1016/j.cell.2016.10.002 · DOI
  29. Lott, 2011, The importin β binding domain as a master regulator of nucleocytoplasmic transport, Biochimica et Biophysica Acta, 1813, 1578, 10.1016/j.bbamcr.2010.10.012 · DOI
  30. Mori, 2013, The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS, Science, 339, 1335, 10.1126/science.1232927 · DOI
  31. Nanaura, 2021, C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers, Nature Communications, 12, 10.1038/s41467-021-25560-0 · DOI
  32. O’Reilly, 2011, Evolution of the karyopherin-β family of nucleocytoplasmic transport factors; ancient origins and continued specialization, PLOS ONE, 6, 10.1371/journal.pone.0019308 · DOI
  33. Popken, 2015, Size-dependent leak of soluble and membrane proteins through the yeast nuclear pore complex, Molecular Biology of the Cell, 26, 1386, 10.1091/mbc.E14-07-1175 · DOI
  34. Prpar Mihevc, 2017, Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, Brain, 140, 13, 10.1093/brain/aww197 · DOI
  35. Pumroy, 2015, Diversification of importin-α isoforms in cellular trafficking and disease states, The Biochemical Journal, 466, 13, 10.1042/BJ20141186 · DOI
  36. Pumroy, 2015, Molecular determinants for nuclear import of influenza A PB2 by importin α isoforms 3 and 7, Structure, 23, 374, 10.1016/j.str.2014.11.015 · DOI
  37. Renault, 1998, The 1.7 A crystal structure of the regulator of chromosome condensation (RCC1) reveals a seven-bladed propeller, Nature, 392, 97, 10.1038/32204 · DOI
  38. Renton, 2011, A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD, Neuron, 72, 257, 10.1016/j.neuron.2011.09.010 · DOI · Paper page
  39. Ryan, 2022, C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm, Scientific Reports, 12, 10.1038/s41598-022-08724-w · DOI
  40. Seewald, 2002, RanGAP mediates GTP hydrolysis without an arginine finger, Nature, 415, 662, 10.1038/415662a · DOI
  41. Semmelink, 2022, Nuclear Transport under Stress Phenocopies Transport Defects in Models of C9Orf72 ALS, 10.1101/2022.04.13.488135 · DOI
  42. Shi, 2017, Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export, PNAS, 114, E1111, 10.1073/pnas.1620293114 · DOI
  43. Stewart, 2007, Molecular mechanism of the nuclear protein import cycle, Nature Reviews. Molecular Cell Biology, 8, 195, 10.1038/nrm2114 · DOI · Paper page
  44. Strambio-De-Castillia, 2010, The nuclear pore complex: bridging nuclear transport and gene regulation, Nature Reviews. Molecular Cell Biology, 11, 490, 10.1038/nrm2928 · DOI
  45. Swaminathan, 2018, Expression of C9orf72-related dipeptides impairs motor function in a vertebrate model, Human Molecular Genetics, 27, 1754, 10.1093/hmg/ddy083 · DOI
  46. Timney, 2016, Simple rules for passive diffusion through the nuclear pore complex, The Journal of Cell Biology, 215, 57, 10.1083/jcb.201601004 · DOI
  47. Varadi, 2022, AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models, Nucleic Acids Research, 50, D439, 10.1093/nar/gkab1061 · DOI · Paper page
  48. Wen, 2014, Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death, Neuron, 84, 1213, 10.1016/j.neuron.2014.12.010 · DOI
  49. White, 2019, C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function, Molecular Cell, 74, 713, 10.1016/j.molcel.2019.03.019 · DOI
  50. Zhang, 2018, Stress granule assembly disrupts nucleocytoplasmic transport, Cell, 173, 958, 10.1016/j.cell.2018.03.025 · DOI
  51. Zhang, 2018, Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis, Nature Medicine, 24, 1136, 10.1038/s41591-018-0071-1 · DOI
  52. Zhang, 2019, Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity, Science, 363, 10.1126/science.aav2606 · DOI

Metadata

Authors
Jafarinia, H., van der Giessen, E., & Onck, P. R.
Affiliations
  • University of Groningen (NL)
  • Zernike Institute for Advanced Materials, University of Groningen
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-03-14
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.89694.3
OpenAlex
W4392803809
Cited by
2
References
3
Citations by year
2026: 1 · 2024: 1
FWCI
0.54
Type
journal article
Language
en
Open access
Licence
Locations
eLife (publishedVersion, 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, amyotrophic lateral sclerosis, protein-protein binding, coarse-grained molecular dynamics

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