9P3Z

Solution structure of the novel zinc finger from ZC4H2

Summary for 9P3Z

• Entry DOI: 10.2210/pdb9p3z/pdb
• NMR Information: BMRB: 53214
• Descriptor: Zinc finger C4H2 domain-containing protein, ZINC ION (2 entities in total)
• Functional Keywords: hca127 kiaa1166 zard c4 zinc finger, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 3097.10

Authors

Alexandrescu, A.T.,Rua, A.J. (deposition date: 2025-06-14, release date: 2025-08-06, Last modification date: 2025-09-10)

Primary citation

Harris, R.E.,Rua, A.J.,Alexandrescu, A.T.
Zinc-Induced Folding and Solution Structure of the Eponymous Novel Zinc Finger from the ZC4H2 Protein.
Biomolecules, 15:-, 2025

PubMed Abstract: The gene is the site of congenital mutations linked to neurodevelopmental and musculoskeletal pathologies collectively termed ZARD (ZC4H2-Associated Rare Disorders). ZC4H2 consists of a coiled coil and a single novel zinc finger with four cysteines and two histidines, from which the protein obtains its name. Alpha Fold 3 confidently predicts a structure for the zinc finger but also for similarly sized random sequences, providing equivocal information on its folding status. We show using synthetic peptide fragments that the zinc finger of ZC4H2 is genuine and folds upon binding a zinc ion with picomolar affinity. NMR pH titration of histidines and UV-Vis of a cobalt complex of the peptide indicate its four cysteines coordinate zinc, while two histidines do not participate in binding. The experimental NMR structure of the zinc finger has a novel structural motif similar to RANBP2 zinc fingers, in which two orthogonal hairpins each contribute two cysteines to coordinate zinc. Most of the nine ZARD mutations that occur in the ZC4H2 zinc finger are likely to perturb this structure. While the ZC4H2 zinc finger shares the folding motif and cysteine-ligand spacing of the RANBP2 family, it is missing key substrate-binding residues. Unlike the NZF branch of the RANBP2 family, the ZC4H2 zinc finger does not bind ubiquitin. Since the ZC4H2 zinc finger occurs in a single copy, it is also unlikely to bind DNA. Based on sequence homology to the VAB-23 protein, the ZC4H2 zinc finger may bind RNA of a currently undetermined sequence or have alternative functions.

PubMed: 40867536
DOI: 10.3390/biom15081091

Experimental method

SOLUTION NMR