ArticleHuman molecular genetics2008
Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain.
Article in Human molecular genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Expanding the phenotypic spectrum associated with ZIC1 variants: A neurodevelopmental disorder with and without craniosynostosis.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- The multifaceted roles of ZIC genes in cancer: from development regulators to cancer modulators.Discover oncology · 2025Review
- Lactylation of Histone H3k18 and Egr1 Promotes Endothelial Glycocalyx Degradation in Sepsis-Induced Acute Lung Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6.Structure (London, England : 1993) · 2024Article
- Non-coding cause of congenital heart defects: Abnormal RNA splicing with multiple isoforms as a mechanism for heterotaxy.HGG advances · 2024Article
- LST-1 is a bifunctional regulator that feeds back on Notch-dependent transcription to regulateProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Loss of Zic3 impairs planar cell polarity leading to abnormal left-right signaling, heart defects and neural tube defects.Human molecular genetics · 2021Article
- ZNF224 Protein: Multifaceted Functions Based on Its Molecular Partners.Molecules (Basel, Switzerland) · 2021Review
- SUMOylation Potentiates ZIC Protein Activity to Influence Murine Neural Crest Cell Specification.International journal of molecular sciences · 2021Article
- Poly(ADP-ribose)-dependent chromatin unfolding facilitates the association of DNA-binding proteins with DNA at sites of damage.Nucleic acids research · 2019Article
- A novel ZIC3 gene mutation identified in patients with heterotaxy and congenital heart disease.Scientific reports · 2018Article
- ZIC3 in Heterotaxy.Advances in experimental medicine and biology · 2018Review
- Article
- Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1.Biochemical and biophysical research communications · 2017Article
- NLScore: a novel quantitative algorithm based on 3 dimensional structural determinants to predict the probability of nuclear localization in proteins containing classical nuclear localization signals.Journal of molecular modeling · 2017Article
- Rare novel variants in the ZIC3 gene cause X-linked heterotaxy.European journal of human genetics : EJHG · 2016Article
- Barriers to Liposomal Gene Delivery: from Application Site to the Target.Iranian journal of pharmaceutical research : IJPR · 2016Review
- Changing Faces of Transcriptional Regulation Reflected by Zic3.Current genomics · 2015Article
- Diversification of importin-α isoforms in cellular trafficking and disease states.The Biochemical journal · 2015Review
- Genetic and functional analyses of ZIC3 variants in congenital heart disease.Human mutation · 2014Article
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Authors and funding
11 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Disruptions in ZIC3 cause heterotaxy, a congenital anomaly of the left-right axis. ZIC3 encodes a nuclear protein with a zinc finger (ZF) domain that contains five tandem C2H2 ZF motifs. Missense mutations in the first ZF motif (ZF1) result in defective nuclear localization, which may underlie the pathogenesis of heterotaxy. Here we revealed the structural and functional basis of the nuclear localization signal (NLS) of ZIC3 and investigated its relationship to the defect caused by ZF1 mutation. The ZIC3 NLS was located in the ZF2 and ZF3 regions, rather than ZF1. Several basic residues interspersed throughout these regions were responsible for the nuclear localization, but R320, K337 and R350 were particularly important. NMR structure analysis revealed that ZF1-4 had a similar structure to GLI ZF, and the basic side chains of the NLS clustered together in two regions on the protein surface, similar to classical bipartite NLSs. Among the residues for the ZF1 mutations, C253 and H286 were positioned for the metal chelation, whereas W255 was positioned in the hydrophobic core formed by ZF1 and ZF2. Tryptophan 255 was a highly conserved inter-finger connector and formed part of a structural motif (tandem CXW-C-H-H) that is shared with GLI, Glis and some fungal ZF proteins. Furthermore, we found that knockdown of Karyopherin alpha1/alpha6 impaired ZIC3 nuclear localization, and physical interactions between the NLS and the nuclear import adapter proteins were disturbed by mutations in the NLS but not by W255G. These results indicate that ZIC3 is imported into the cell nucleus by the Karyopherin (Importin) system and that the impaired nuclear localization by the ZF1 mutation is not due to a direct influence on the NLS.
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