ArticleProceedings of the National Academy of Sciences of the United States of America2012
Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 146 citations in OpenAlex.
- Multiple roads between the nucleus and the cytoplasm: classes of linear NLSs and NESs and their receptors.Current opinion in structural biology · 2026Review
- Learning the PTM code through a coarse-to-fine mechanism-aware framework.Nature communications · 2026Article
- Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.bioRxiv : the preprint server for biology · 2025Article
- [Heterogeneity in the regulation of cellular stress responses byZhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Article
- Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.Molecular neurobiology · 2025Article
- DeepMVP: deep learning models trained on high-quality data accurately predict PTM sites and variant-induced alterations.Nature methods · 2025Article
- Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5.Nature communications · 2025Article
- NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.Communications biology · 2025Article
- Neurological Diseases can be Regulated by Phase Separation.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.Nature communications · 2024Article
- Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.International journal of molecular sciences · 2024Review
- Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA-protein interactions.Cellular and molecular life sciences : CMLS · 2024Article
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
- A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders.Structure (London, England : 1993) · 2023Article
- Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing.Frontiers in cell and developmental biology · 2023Review
- FUS-P525L Juvenile Amyotrophic Lateral Sclerosis and Intellectual Disability: Evidence for Association and Oligogenic Inheritance.Neurology. Genetics · 2022Article
- Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.Biology · 2022Review
- Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.Nature communications · 2022Article
- A FRET-based method for monitoring structural transitions in protein self-organization.Cell reports methods · 2022Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
Mutations in the proline/tyrosine-nuclear localization signal (PY-NLS) of the Fused in Sarcoma protein (FUS) cause amyotrophic lateral sclerosis (ALS). Here we report the crystal structure of the FUS PY-NLS bound to its nuclear import receptor Karyopherinβ2 (Kapβ2; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kapβ2, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kapβ2 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn α-helix. The Kapβ2-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif, a central arginine-rich α-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kapβ2 and mutations of these residues decrease binding affinities for Kapβ2 (K(D) for wild-type FUS PY-NLS is 9.5 nM) up to ninefold. Thermodynamic analyses of ALS mutations in the FUS PY-NLS show that the weakening of FUS-Kapβ2 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.
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