Zinc finger protein 804A is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''ZNF804A''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. The human gene maps to

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost e ...

q32.1 and consists of 4 exons that code for a protein of 1210 amino acids (137 kDa). Little is known about the characteristics and function of the encoded protein. However, the protein sequence codes for a domain characteristic of a classical C₂H₂-type

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

near the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

end.

Interactions

ZNF804A binds to the N-terminus of

ATXN1 Ataxin-1 is a DNA-binding protein which in humans is encoded by the ''ATXN1'' gene. Mutations in ataxin-1 cause spinocerebellar ataxia type 1, an inherited neurodegenerative disease characterized by a progressive loss of cerebellar neurons, parti ...

Binding of DNA

The tertiary structure of the C₂H₂ finger consists of a

beta hairpin The beta hairpin (sometimes also called beta-ribbon or beta-beta unit) is a simple protein structural motif involving two beta strands that look like a hairpin. The motif consists of two strands that are adjacent in primary structure, oriented in ...

folded against an

alpha helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

. The folding occurs via a

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

(II) ion that coordinates to two

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

residues (one on each

beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...

) and two

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

residues (both on the α-helix). ZNF804A might use its zinc finger to bind DNA in a sequence-specific manner. For example, Carl Pabo and his colleagues in 1991 discovered that mouse transcription factor

Zif268 EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It wa ...

binds DNA using three linked C₂H₂ zinc fingers. Amino acid residues sticking out from the α-helices of the zinc fingers interact with the guanine-rich region of the DNA double helix through hydrogen bonds and electrostatic and hydrophobic interactions. The spacing of the residues matches the spacing of the base pairs. Zinc fingers fit into the major groove and wrap around the DNA helix for almost one turn.

Association with schizophrenia

In humans, ZNF804A is expressed broadly throughout the brain, especially in the developing hippocampus and the cortex, as well as in the adult

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

. ZNF804A is expected to bind DNA and thus regulate gene expression like other zinc finger proteins. The mouse homologue of ZNF804A, zfp804a, has recently been reported as a target for HOXC8, suggesting that ZNF804A may be involved in the regulation of early neurodevelopment. A

Genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different i ...

(GWAS) has identified ZNF804A as a susceptibility gene for schizophrenia. From family, twin, and adoption studies,

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

is found to have heritability of ~80% and it is suspected that risk results from multiple genetic variants of small effect. The

single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...

(SNP) rs1344706 in

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

2 of ZNF804A has been identified as a variant that is most strongly associated with schizophrenia. The same SNP has been reported to correlate with slightly disturbed ''functional coupling'' of several brain regions in healthy persons, resembling the changes described in

. * A further study revealed that the SNP rs1344706 was consistent with schizophrenia association in European patients, but not in Han Chinese patients. Moreover, the study showed that SNPs rs1021042 and rs359895 are associated with schizophrenia in Han Chinese patients, and that the rs359895 allele increases the promoter activity of ZNF804A. The results of another study suggest that there is no relationship between variant rs1344706 and impaired cognitive function in schizophrenia patients and the results of yet another study indicate that ZNF804A also plays a role in how schizophrenia symptoms respond to antipsychotics.

References

{{Transcription factors and intracellular receptors, g2 Proteins