The Tandem Zinc-Finger Region of Human ZHX Adopts a Novel C2H2 Zinc Finger Structure with a C-Terminal Extension

Binding of the nuclear factor-Y complex (NF-Y) to the inverted CCAAT-box interferes with transcription activation through nucleosome reorganization. The three homologous proteins forming the zinc-fingers and homeoboxes (ZHX) family interact with the activation domain of NF-Ya to repress transcriptio...

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Bibliographic Details
Published in:Biochemistry (Easton) 2009-06, Vol.48 (21), p.4431-4439
Main Authors: Wienk, Hans, Lammers, Ivonne, Hotze, Anna, Wu, Jin, Wechselberger, Rainer W, Owens, Ray, Stammers, David K, Stuart, David, Kaptein, Robert, Folkers, Gert E
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Conserved Sequence
Homeodomain Proteins - chemistry
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Models, Molecular
Molecular Sequence Data
Mutation
Sequence Homology, Amino Acid
Substrate Specificity
Transcription Factors - chemistry
Transcription Factors - genetics
Transcription Factors - metabolism
Zinc Fingers
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Summary:Binding of the nuclear factor-Y complex (NF-Y) to the inverted CCAAT-box interferes with transcription activation through nucleosome reorganization. The three homologous proteins forming the zinc-fingers and homeoboxes (ZHX) family interact with the activation domain of NF-Ya to repress transcription. Each ZHX-protein contains two generic C2H2 zinc-fingers (ZNF1 and ZNF2) followed by five homeodomains. Although the proteins have been related to the occurrence of certain cancers, the function and structure of the individual ZHX domains are still unknown. Here, we determined the structure of the tandem zinc-finger region of human ZHX1. Folding and secondary structure predictions combined with expression screening revealed that the C-terminal extension (E) to ZNF2 could form a single domain with the two hZHX1 zinc-fingers. We therefore decided to determine the solution structure of the zinc-fingers followed by this extension. We show that both zinc-fingers adopt canonical ββα-folds in which a zinc ion is coordinated by two cysteine and two histidine residues. The C-terminal extension to ZNF2 forms two β-strands to make a β-sheet with the β-strands of this zinc-finger. The ZNF1 and ZNF2-E domains do not show evident contacts and their mutual orientation seems variable. The high degree of sequence conservation among ZHX family members permitted us to prepare homology models for ZHX2 and ZHX3, revealing distinct surface characteristics for each family member. Implications of these structural features for ZHX-functioning in transcription regulation are discussed.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi9001997