Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain.

Human Molecular Genetics
Minoru HatayamaJ Aruga

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 ...Continue Reading

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Citations

Feb 22, 2011·Neurochemical Research·Jun Aruga, Katsuhiko Mikoshiba
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Feb 20, 2010·BMC Evolutionary Biology·Minoru Hatayama, Jun Aruga
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Feb 1, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Areli AguilarBulmaro Cisneros
Aug 28, 2021·Stem Cell Reviews and Reports·Ping HuangPing Zhu
Oct 30, 2021·Journal of Cell Science·Piotr GrabarczykChristian Andreas Schmidt

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Methods Mentioned

BETA
Circular dichroism
NMR
pull-down
protein folding
PCR
transfection

Software Mentioned

NMRPipe
Image
- NMR
CYANA
PhotoshopCS
NMRView
KUJIRA
PROCHECK

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