Zinc Finger Protein 548 (ZNF548) is a human protein encoded by the ZNF548 gene which is located on chromosome 19.[1] 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.[2]
This protein coding gene is 4987 bp long and encodes transcript variant 1 which is the longest ZNF548 isoform.[3] [4] 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.[5] [6]
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: Rhesus macaque (rhesus monkey), Pan troglodytes (chimpanzee), Oryctolagus cuniculus (European rabbit), Equus caballus (horse), Canis lupus familiaris (dog) and Sus scrofa (pig).[7]
Transcript variant 1 is the longest transcript and encodes the longest protein isoform (ZNF548 isoform 1) which is 545 amino acids long. Transcript variant 2 is missing exon 2 and encodes ZNF548 isoform 2 which is 533 amino acids long.[8] [9]
ZNF548 belongs to the Kruppel C2H2-type zinc finger protein family as it contains 11 Cys2His2-type zinc finger repeats. 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.[10] 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.[11]
Tertiary structure of ZNF548 was predicted using I-Tasser.[12] [13]
ZNF548 has a molecular weight of 64 kDa and a predicted isoelectric point of 8.21.[14] 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.[15]
The protein is found in the nucleus and could also be detected in the cytoplasm or the mitochondria.[16] [17]
ZNF548 expression in humans is relatively low compared to other proteins.[18] It has low tissue specificity; it is expressed and detected in all human tissues.[19]
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.[20] 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.[21]
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.[22] [23]
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.[23]
The KRAB domain as well as the zinc finger repeats are highly conserved across orthologs.
| 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 |
ZNF548 has 25 paralogous proteins in human as seen in the table below.
| 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 |
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.[25]
ZNF548 microRNA expression can act as a marker to diagnose ovarian cancer.[26] ZNF548 blood gene expression biomarker can also be used as a marker for suicidality.[27]