| NBPF1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | NBPF1 , AB13, AB14, AB23, AD2, NBG, NBPF, neuroblastoma breakpoint family member 1, NBPF member 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 610501 HomoloGene: 41035 GeneCards: NBPF1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Neuroblastoma breakpoint family, member 1, or NBPF1, is a protein that is encoded by the gene NBPF1 in humans. This protein is member of the neuroblastoma breakpoint family of proteins, a group of proteins that are thought to be involved in the development of the nervous system. [3]
The NBPF1 gene in humans is located on the minus strand of 1p36.3 in humans and is 51179 base pairs long including exons and introns. It is located between the protein coding genes NECAP2 and CROCC. NBPF1 is one of the 26 known members of the Neuroblastoma Breakpoint Family genes and pseudogenes. The NBPF2 pseudogene and NBPF3 gene are the most similar genes located close to NBPF1 and they reside on the chromosomal location 1p36.12. Most members of the NBPF gene family are located on chromosomal location 1q21.1-1q23.3 in humans, and these genes are more similar to each other in sequence than they are to NBPF1. [4]
The transcript for NBPF1 in humans is a 6183 base pair mRNA that is made of 28 exons. There are more than 14 alternative splicing forms of NBPF1 predicted, but only seven of the splice forms have been observed. Out of all of the possible transcripts, only two are known to code proteins. One of these transcripts is 1139 amino acids long with 23 coding exons, while and the other is 1095 amino acids long and 23 coding exons. The noncoding transcripts are processed, but their function is unknown. [3] [5] [6]
NBPF1 is a 1214 amino acid long protein in humans that weighs 139 kD and has an isoelectric point of around 5. A feature about this protein's composition is that it is much richer than most other proteins in both glutamine and glutamic acid residues. Additionally, it contains amino acid repeats that are present in humans, other primates, and even armadillos. [7] Another feature is that the NBPF1 protein contains residues that are predicted to have post-translational modifications, including glycation, N-linked glycosylation, O-GlcNAc attachment, O-linked glycosylation, Phosphorylation, and Sumoylation. [8] The two most important domain types in the NBPF1 protein are the coiled coil domains and DUF1220 domains. NBPF1 contains three coiled coil domains and nine DUF1220 domains in humans. The coiled coil domains are 60-100 amino acids long, while the DUF1220 domains are approximately 65 base pairs long with high sequence similarity. [9]
Human NBPF1 has been shown to interact with Ubiquitin C via both protein complex immunoprecipitation [10] and affinity chromatography. [11] Two-hybrid screening assays have shown that NBPF1 interacts with the coiled coil domains of CBY1, a repressor for the Beta-catenin, a protein that is involved in Wnt signaling for cell proliferation. [12] Additionally, two hybrid screen have shown that NBPF1 interacted with bacterial proteins, such as an Oxidoreductase iron/ascorbate family protein from the bacterium Francisella tularensis and an uncharacterized protein from the bacterium Bacillus anthracis. [13]
Although the function of the NBPF1 protein in unknown, its physical and chemical properties can give insight about its function. Like other NBPF proteins, the NBPF1 protein product contains a repeated domain called DUF1220, a domain of unknown function that is thought to be related to human brain complexity. [14] First, NBPF1 is predicted to be a nuclear protein, as it contains positively charged nuclear localization signals. These nuclear localization signals in NBPF1 and a conserved DNA binding domain similar to the transcription factor STAT3/dna complex or STAT1/dna complex suggests that it could act as a transcription factor [15]
Second, genes like NBPF1 with DUF1220 genes are expressed during human neurogenesis. The number of DUF1220 domains present in the human genome correlates with both brain size and the amount of neurons present in the brain. [16] Additionally, higher copy numbers of the DUF1220 domain are associated with increasing Autism severity, which often results from an excess of neurons that do not under synaptic pruning. [17]
The NBPF1 protein is also found to be disrupted by a chromosomal translocation between chromosomes 1 and 17 with in some cases of human neuroblastoma. [18] Additional studies show that NBPF1 is possibly a tumor suppressor gene because adding it to cell cultures lowers the incidence of foci formation. Additionally, NBPF1 contains three coiled coil structures are commonly involved in oligomerization with other proteins. [19] Based on the interactions listed above, NBPF1 is shown to interact with the coiled coil domain of CBY1, which represses Wnt signaling. [18] Aberrant Wnt signaling in the brain is a common cause of tumor growth and drug resistance in neuroblastomas, [20] further suggesting that NBPF1 could act as a tumor suppressor gene in the brain if it directly affects this pathway.
NBPF1 seems to be involved in proliferation during human neurogenesis, and growth suppression during adulthood. Showing that the DUF1220 and coiled coil domains may be important during different life stages. The DUF1220 domains are important in neurogenesis, while the coiled coil domains involved with the binding of cell proliferation inhibitors. Although there are no known differences between Autism and neuroblastoma rates are known, a study has shown the existence of comorbid microcephaly and neuroblastoma conditions, although more research is needed to show this. [21] Based on these predictions, the lack of NBPF1 during could prevent fetal neurogenesis and postnatal tumor suppression in the brain, although this connection is not well understood.
NBPF1 is ubiquitously expressed in all tissues in humans, but shows the highest levels of expression in the bone marrow, skeletal muscle, brain, and spinal cord. It is expressed at slightly lower levels in other tissues such as the pancreas, kidney, and lung. [22] In the brain, NBPF1 expression is the highest in the frontal, temporal, and parietal lobes, and it lowest in the ventricles and cerebellum. [23] Based on protein composition, NBPF1 in humans and its orthologs in related species is most likely to be localized in the nucleus. [24]
Predicted Localization of NBPF1 and its Orthologs [24]
| Species | %Nuclear | %Vacuolar | %Cytoplasmic | %Cytoskeletal |
|---|---|---|---|---|
| Human | 87.0 | 4.3 | 4.3 | 4.3 |
| Macaque | 65.2 | 4.3 | 17.4 | 4.3 |
| Baboon | 82.6 | 0.0 | 13.0 | 0.0 |
| Cow | 65.2 | 0.0 | 17.4 | 0.0 |
| Armadillo | 65.2 | 0.0 | 13.0 | 0.0 |
Expression studies have shown changes in NBPF1 under different experimental conditions in vitro. First, the depletion of nervous system transcription factor SOX11 causes a slight increase in NBPF1 expression. [25] Additionally, the inactivation of Far upstream element-binding protein 1 causes a decrease in NBPF1, while the inactivation of Far Upstream Binding Elements 2 and 3 causes an increase in NBPF1 expression. [26] Far upstream binding elements are involved in transcriptional regulation using gene enhancers, each having different binding sites. [27] The overexpression of CLDN1, a protein that forms tight junctions such as those of the blood–brain barrier, causes a sharp decline in NBPF1 expression [28]
Although NBPF1 itself only exists in primates, a wide variety of NBPF like protein orthologs exist in other mammals such as cattle, felines, and cetaceans. In non-primate mammals, the gene sequences of NBPF-like genes have little similarity to the primate NBPF genes. These genes appear to be entirely absent in model mammals such as mice and rats. The large amount of NBPF genes in the human genome is most likely due to recent duplications because all of the NBPF genes are so similar and repetitive that they easily recombine with each other, causing duplications. Variation in the number of repetitive sequences in the NBPF genes also varies even within humans. [29] DUF1220 domains also vary greatly from humans in other species in their NBPF proteins. The further away a species is from humans, the fewer DUF1220 domains the species has. Humans have on average 272 DUF1220 domains in their NBPF genes, while chimpanzees have 125, macaques have 35, and dolphins only have 4. [30]
Selected Orthologs of NBPF1 [31] [32]
| Species | Common name | Time of divergence from humans (mya) | NCBI accession number | Sequence length (amino acids) | Protein similarity to human NBPF1 | mRNA similarity to human NBPF1 |
|---|---|---|---|---|---|---|
| Homo sapiens | Human | 0 | AAX85114.1 | 1214 | 100% | 100% |
| Pan troglodytes | Chimpanzee | 6.3 | XP_009439437.1 | 656 | 93% | 98% |
| Macaca fascicularis | Crab-eating macaque | 29 | XP_005544713.1 | 1173 | 77% | 87% |
| Tursiops truncates | Bottle-nosed dolphin | 94.2 | XP_004329243.1 | 888 | 40% | 37% |
| Bos taurus | Cattle | 94.2 | XP_005197798.1 | 633 | 39% | 36% |
| Felis catus | Domestic cat | 94.2 | XP_011283477.1 | 813 | 38% | 35% |
| Sus scrofa | Pig | 94.2 | XP_005653139.1 | 567 | 36% | 40% |
| Dasypus novemcinctus | Nine-banded armadillo | 104.2 | XP_004469026 | 934 | 30% | 34% |
The paralogs for NBPF1 are other members of the NBPF protein family. The highest similarity between these paralogs further shows evidence of gene duplication during human evolution.
Selected Paralogs of NBPF1
| Gene name | NCBI accession number | Sequence length (amino acids) | Protein sequence identity | Protein sequence similarity |
|---|---|---|---|---|
| NBPF1 | NP_060410.2 | 1214 | 100% | 100% |
| NBPF12 | NP_001265070.1 | 1457 | 100% | 93% |
| NBPF8 | NP_001032590.2 | 942 | 100% | 93% |
| NBPF14 | NP_056198.2 | 2819 | 100% | 92% |
| NBPF15 | NP_775909.2 | 670 | 98% | 93% |
| NBPF3 | NP_115640.1 | 633 | 100% | 75% |
The Olduvai domain, known until 2018 as DUF1220 and the NBPF repeat, is a protein domain that shows a striking human lineage-specific (HLS) increase in copy number and appears to be involved in human brain evolution. The protein domain has also been linked to several neurogenetic disorders such as schizophrenia and increased severity of autism. In 2018, it was named by its discoverers after Olduvai Gorge in Tanzania, one of the most important archaeological sites for early humans, to reflect data indicating its role in human brain size and evolution.
N-myc proto-oncogene protein also known as N-Myc or basic helix-loop-helix protein 37 (bHLHe37), is a protein that in humans is encoded by the MYCN gene.
Transcriptional regulator Kaiso is a protein that in humans is encoded by the ZBTB33 gene. This gene encodes a transcriptional regulator with bimodal DNA-binding specificity, which binds to methylated CGCG and also to the non-methylated consensus KAISO-binding site TCCTGCNA. The protein contains an N-terminal POZ/BTB domain and 3 C-terminal zinc finger motifs. It recruits the N-CoR repressor complex to promote histone deacetylation and the formation of repressive chromatin structures in target gene promoters. It may contribute to the repression of target genes of the Wnt signaling pathway, and may also activate transcription of a subset of target genes by the recruitment of catenin delta-2 (CTNND2). Its interaction with catenin delta-1 (CTNND1) inhibits binding to both methylated and non-methylated DNA. It also interacts directly with the nuclear import receptor Importin-α2, which may mediate nuclear import of this protein. Alternatively spliced transcript variants encoding the same protein have been identified.
Neuroblastoma breakpoint family, member 3, also known as NBPF3, is a human gene of the neuroblastoma breakpoint family, which resides on chromosome 1 of the human genome. NBPF3 is located at 1p36.12, immediately upstream of genes ALPL and RAP1GAP.
MAP11 is a protein that in human is encoded by the gene MAP11. It was previously referred to by the generic name C7orf43. C7orf43 has no other human alias, but in mice can be found as BC037034.
Neuroblastoma breakpoint family, member 15, also known as NBPF15, is a protein which in humans is encoded by the NBPF15 gene. The gene is 18762 bp long, with mRNA that is 3837 bp long. The gene is located on chromosome 1q21.1. Its sub-cellular location is predicted to be in the nucleus and cytoplasm. It contains what is known as the NBPF repeat, which is a two-exon stretch of sequence that is characteristic of all 21 members of the NBPF gene family. The repeat is considered the ancestral exons, and the NBPF family has been linked to primate evolution.
Neuroblastoma breakpoint family member 10 is a protein that in Homo sapiens is encoded by the NBPF10 gene.
Coiled-coil domain containing 109B (CCDC109B) is a potential calcium uniporter protein found in the membrane of human cells and is encoded by the CCDC109B gene. While CCDC109B is a transmembrane protein it is unclear if it is located within the cell membrane or mitochondrial membrane.
TMEM143 is a protein that in humans is encoded by TMEM143 gene. TMEM143, a dual-pass protein, is predicted to reside in the mitochondria and high expression has been found in both human skeletal muscle and the heart. Interaction with other proteins indicate that TMEM143 could potentially play a role in tumor suppression/expression and cancer regulation.
FAM76A is a protein that in Homo sapiens is encoded by the FAM76A gene. Notable structural characteristics of FAM76A include an 83 amino acid coiled coil domain as well as a four amino acid poly-serine compositional bias. FAM76A is conserved in most chordates but it is not found in other deuterostrome phlya such as echinodermata, hemichordata, or xenacoelomorpha—suggesting that FAM76A arose sometime after chordates in the evolutionary lineage. Furthermore, FAM76A is not found in fungi, plants, archaea, or bacteria. FAM76A is predicted to localize to the nucleus and may play a role in regulating transcription.
Chromosome 15 open reading frame 52 is a human protein encoded by the C15orf52 gene, its function is poorly understood.
Uncharacterized protein C12orf60 is a protein that in humans is encoded by the C12orf60 gene. The gene is also known as LOC144608 or MGC47869. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus.
Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
Retroelement silencing factor 1 is a protein that in humans is encoded by the RESF1 gene. RESF1 is broadly expressed in the lymph nodes, ovaries, appendix and spleen. RESF1 shows characteristics of being a minor histocompatibility antigen, as well as tumor suppressor capabilities. The high expression in the lymph nodes and spleen indicate function in the immune system.
Neuroblastoma breakpoint family member 19, or NBPF19, is a protein that in humans is encoded by the NBPF19 gene. This protein is included in the neuroblastoma breakpoint family of proteins.
Coiled-coil domain containing 60 is a protein that in humans is encoded by the CCDC60 gene that is most highly expressed in the trachea, salivary glands, bladder, cervix, and epididymis.
C13orf38 is a protein found in the thirteenth chromosome with an open reading frame number 38. It is 139 amino acids long. The protein goes by a number of aliases CCDC169-SOHLH2 and CCDC169. The protein is found to be over expressed in the testis of humans. It is not known what the exact function of the protein is at this current time. The human CCDC169 gene contains 753 nucleotides. C13orf contains a domain of unknown function DUF4600. which is conserved in between nucleotide interval 1-79. The protein contains 139 amino acids.
The neuroblastoma breaking point family (NBPF) is a family of genes involved in neuronal development. The family is highly specific to primates, with minimal similarity or presence in other mammals and no presence in other animals, and its genes' content has been subject to a very high number of duplications in humans. It was described by Vandepoele et al. in 2005 and named as such because NBPF1 was found to be broken by a chromosomal translocation in a neuroblastoma patient.
WD Repeat and Coiled-coiled containing protein (WDCP) is a protein which in humans is encoded by the WDCP gene. The function of the protein is not completely understood, but WDCP has been identified in a fusion protein with anaplastic lymphoma kinase found in colorectal cancer. WDCP has also been identified in the MRN complex, which processes double-stranded breaks in DNA.
Coiled-Coil Domain Containing 190, also known as C1orf110, the Chromosome 1 Open Reading Frame 110, MGC48998 and CCDC190, is found to be a protein coding gene widely expressed in vertebrates. RNA-seq gene expression profile shows that this gene selectively expressed in different organs of human body like lung brain and heart. The expression product of c1orf110 is often called Coiled-coil domain-containing protein 190 with a size of 302 aa. It may get the name because a coiled-coil domain is found from position 14 to 72. At least 6 spliced variants of its mRNA and 3 isoforms of this protein can be identified, which is caused by alternative splicing in human.
