ZNF548

Zinc Finger Protein 548 (ZNF548) is a human protein encoded by the ZNF548 gene which is located on chromosome 19.^[3] It is found in the nucleus and is hypothesized to play a role in the regulation of transcription by RNA Polymerase II. It belongs to the Krüppel C2H2-type zinc-finger protein family as it contains many zinc-finger repeats.^[4]

ZNF548
Identifiers
Aliases	ZNF548, zinc finger protein 548
External IDs	HomoloGene: 122790; GeneCards: ZNF548; OMA:ZNF548 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.43 Start 57,389,850 bp[1] End 57,402,992 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gingival epithelium buccal mucosa cell superficial temporal artery germinal epithelium mucosa of paranasal sinus cardia lower lobe of lung subthalamic nucleus external globus pallidus lateral nuclear group of thalamus n/a More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding metal ion binding nucleic acid binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component intracellular anatomical structure nucleus Biological process transcription, DNA-templated regulation of transcription, DNA-templated regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 147694 n/a Ensembl ENSG00000188785 n/a UniProt Q8NEK5 n/a RefSeq (mRNA) NM_152909 NM_001172773 n/a RefSeq (protein) NP_001166244 NP_690873 n/a Location (UCSC) Chr 19: 57.39 – 57.4 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

ZNF548 schematic illustration made with DOG 2.0. Blue represents the KRAB domain while pink represents the 11 zinc fingers found in the human ZNF548 protein that is 545 amino acids long.

Gene

This protein coding gene is 4987 bp long and encodes transcript variant 1 which is the longest ZNF548 isoform.^[5][6] It is found on chromosome 19; its exact position is 19q13.43 in the plus strand. The gene has 4 exons which encode for a Kruppel associated box (KRAB domain) and 11 zinc finger repeats.^[7][8]

Promoter

The promoter of the ZNF548 gene is 1198 bases long and is located at 57388850 - 57390047 on chromosome 19. The promoter region is conserved in 6 orthologs: Macaca mulatta (rhesus monkey), Pan troglodytes (chimpanzee), Oryctolagus cuniculus (European rabbit), Equus caballus (horse), Canis lupus familiaris (dog) and Sus scrofa (pig).^[9]

Transcript

Conceptual translation of the Human ZNF548 isoform 1 protein. DNA sequence at the beginning is the 5' UTR while DNA sequence at the end is the 3' UTR. Below the DNA sequence the amino acids encoded by each codon are shown. Annotations in the figure include: an upstream in-frame stop, start and stop codons, exon boundaries, amino acids missing in ZNF548 isoform 2, the KRAB domain, the 11 zinc fingers which are also annotated as internal repeats, zinc finger double domains, zinc binding sites, putative nucleic acid binding sites, poly-A signals and poly-A sites.

Transcript variant 1 is the longest transcript and encodes the longest protein isoform (ZNF548 isoform 1) which is 545 amino acids long.^[5][10] Transcript variant 2 is missing exon 2 and encodes ZNF548 isoform 2 which is 533 amino acids long.^[11][12]

Protein

ZNF548 belongs to the Kruppel C2H2-type zinc finger protein family as it contains 11 Cys2His2-type zinc finger repeats.^[4] Each zinc finger has a conserved ββα structure where a zinc atom is fixed by C2H2 residues. ZNF548 is able to attach to the DNA at a 44 bp long sequence through its C2H2 Zn motifs, each binding to 4 DNA bases.^[13] The protein also contains a Kruppel-associated box (KRAB) which is a domain found at the N terminus and contains multiple charged amino acids. This domain plays a role in transcription; it binds to the RING-B box-coiled coil (RBCC) domain of the KAP-1/TIF1-beta co-repressor.^[14]

ZNF548 tertiary structure predicted by I-Tasser.^[15] The structure was edited in iCn3D so the orange color represents the KRAB domain while blue represents the 11 zinc fingers found in the human ZNF548 protein.

Tertiary structure of ZNF548 was predicted using I-Tasser.^[16][17]

ZNF548 has a molecular weight of 64 kDa and a predicted isoelectric point of 8.21.^[18] Compositional analysis of ZNF548 revealed that Alanine was found at a lower percentage than expected while Histidine was found at a much higher percentage than expected in the human ZNF548.^[19]

Subcellular expression

The protein is found in the nucleus and could also be detected in the cytoplasm or the mitochondria.^[20][21]

Tissue expression

ZNF548 expression in humans is relatively low compared to other proteins.^[22] It has low tissue specificity; it is expressed and detected in all human tissues.^[23]

Interactions with other proteins

Interaction of the human ZNF548 protein with the Nuclear distribution protein nudE-like 1 (NDEL1) and the Disrupted in schizophrenia 1 (DISC1) proteins has been experimentally validated using the two hybrid fragment pooling approach.^[24] Leucine rich repeat containing 36 (LRRC36), Myotubularin 1 (MTM1), Myotubularin related protein 4 (MTMR4) and RNA binding motif protein 39 (RBM39) have also been detected to interact with the ZNF548 protein through Affinity Capture-Mass Spectrometry.^[25]

Function

ZNF548 has been associated with gene expression as it can bind to nucleic acids as well as zinc ions. Based on the function of other KRAB-ZNF proteins it is hypothesized that it plays a role in the regulation of transcription of protein-encoding genes transcribed by RNA Polymerase II. Specifically it is a DNA-binding transcription factor that enhances or inhibits the transcription of certain genes that are transcribed by RNA Polymerase II. It has the ability to bind to a transcription factor recognition sequence that is on the same strand (cis) as the transcription start site via its zinc-fingers and become part of the KRAB-ZNF/KAP complex in the nucleoplasm. KRAB-ZNF proteins are known to be repressors. Therefore, when a KRAB-ZNF protein, such as ZNF548, is bound to DNA and simultaneously binds to the KAP1 co-repressor through its KRAB domain, various enzymes, such as histone deacetylases, histone methyltransferases and heterochromatin proteins, are recruited in order to compact the chromatin structure and consequently prevent transcription.^{[3][4][10][26][27]}

Homologs

Orthologs

Orthologs of the ZNF548 protein have been found conserved across different orders of mammals only. This is line with the fact that C2H2-like fold groups are very common in mammalian transcription factors.^[28]

The KRAB domain as well as the zinc finger repeats are highly conserved across orthologs.

ZNF548 Ortholog table

Genus, Species	Common name	Order	Estimated divergence date (MYA)	Accession number[29]	Sequence length (aa)	Sequence similarity to human protein (%)
Homo sapiens	Human	Primates	0	NP_001166244.1	545	100
Pan troglodytes	Chimpanzee	Primates	6.7	XP_003316775.1	545	99.3
Rhinopithecus roxellana	Golden snub-nosed monkey	Primates	29.44	XP_010385311.1	545	97.8
Cercocebus atys	Sooty mangabey	Primates	29.44	XP_011931548.1	545	97.6
Trachypithecus francoisi	François' langur	Primates	29.44	XP_033080506.1	545	97.8
Oryctolagus cuniculus	European rabbit	Lagomorpha	90	XP_017193400.1	532	84.2
Marmota monax	Groundhog	Rodentia	90	KAF7471703.1	546	84.9
Ictidomys tridecemlineatus	Thirteen-lined ground squirrel	Rodentia	90	XP_013221367.2	546	84.9
Octodon degus	Common degu	Rodentia	90	XP_012368689.1	548	81.1
Castor canadensis	North American beaver	Rodentia	90	XP_020025721.1	545	76
Heterocephalus glaber	Naked mole-rat	Rodentia	90	XP_012921729.1	599	77.1
Enhydra lutris kenyoni	Sea otter	Carnivora	96	XP_022347780.1	583	76
Leptonychotes weddellii	Weddell seal	Carnivora	96	XP_030883405.1	634	66.4
Ailuropoda melanoleuca	Giant panda	Carnivora	96	XP_034495390.1	630	65.6
Equus przewalskii	Przewalski's horse	Perissodactyla	96	XP_008522443.1	579	71.4
Ceratotherium simum simum	Southern white rhinoceros	Perissodactyla	96	XP_014649872.1	578	71.1
Physeter catodon	Sperm whale	Artiodactyla	96	XP_023972760.1	589	72.5
Balaenoptera musculus	Blue whale	Artiodactyla	96	XP_036688369.1	592	72.3
Lipotes vexillifer	Baiji	Artiodactyla	96	XP_007457531.1	582	72.1
Bos taurus	Cattle	Artiodactyla	96	NP_001193737.1	581	70.3
Pteropus alecto	Black flying fox	Chiroptera	96	XP_024905354.1	678	64.1

Paralogs

ZNF548 has 25 paralogous proteins in human as seen in the table below.

ZNF548 Paralog Table

Protein name	Accession number	Sequence similarity to human ZNF548 protein (%)
ZNF548	NP_001166244.1	100
ZIK1	NP_001010879.2	57.6
ZNF792	NP_787068.3	56.2
ZNF419	NP_001091961.1	56.2
ZNF154	NP_001078853.1	55.3
ZNF256	NP_005764.2	54.7
ZNF549	NP_001186224.2	52.9
ZNF586	NP_060122.2	52.7
ZNF773	NP_940944.1	52.2
ZNF418	NP_001303956.1	51.6
ZNF480	NP_653285.2	51.6
ZNF551	NP_612356.2	50.7
ZNF304	NP_001277247.1	50.3
ZNF583	NP_001153332.1	49.2
ZNF570	NP_001287922.1	48.9
ZNF772	NP_001019767.1	48.6
ZNF587B	NP_001363152.1	48.6
ZNF79	NP_009066.2	48.4
ZNF8	NP_066575.2	46.4
ZNF584	NP_775819.1	46
ZNF561	NP_689502.2	45.8
ZNF552	NP_079038.2	43
ZNF610	NP_001154897.1	42.6
ZNF793	NP_001013681.2	41.7
ZNF562	NP_001123503.1	41
ZNF691	NP_001229668.1	31.5

Clinical Significance

ZNF548 was identified as a gene in meta-virus signature (MVS) which can be used to distinguish individuals with viral infections from those with bacterial infections as well as from healthy individuals.^[30]

ZNF548 microRNA expression can act as a marker to diagnose ovarian cancer.^[31] ZNF548 blood gene expression biomarker can also be used as a marker for suicidality.^[32]