| DEPDC5 | |||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||||||||||||||||||||||||
| Aliases | DEPDC5 , DEP.5, FFEVF, DEP domain containing 5, FFEVF1, DEP domain containing 5, GATOR1 subcomplex subunit | ||||||||||||||||||||||||||||||
| External IDs | OMIM: 614191; MGI: 2141101; HomoloGene: 34718; GeneCards: DEPDC5; OMA:DEPDC5 - orthologs | ||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| Wikidata | |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
DEPDC5 (or DEP domain-containing 5) is a human protein of poorly understood function but has been associated with cancer in several studies. [5] [6] It is encoded by a gene of the same name, located on chromosome 22.
The function of DEPDC5 is not yet known, but it has been implicated in intracellular signal transduction based on homology between the DEP domains of DEPDC5 and Dishevelled-1 (DVL1). [7]
Mutations in this gene have been associated to cases of focal epilepsy (doi:10.1038/ng.2601).
In Homo sapiens , the DEPDC5 gene has been localized to the long arm of chromosome 22, 22q12.2-q12.3, between the PRRL14 and YWHAH genes. The clinical relevance of this gene includes an intronic SNP (rs1012068) that has been associated with a 2-fold hepatocellular carcinoma-risk increase. [5]
The DEP domain derives its name from the proteins Dishevelled, Egl-10 and Pleckstrin, each of which contain a variant of this domain. [8] It spans 82 residues and is 343 amino acids from the C-terminus. A SWISS-MODEL predicts two beta sheets and three alpha helices contained within the domain. [9]
While its exact function is not known, the DEPDC5 DEP domain has the highest structural similarity to the DEP domain of DVL1 when performing a CBLAST at NCBI. [10] The alignment scores an Evalue of 1.00e-08 and indicates 30% identity between the DEP domains of the two proteins. In DVL1, the DEP domain is involved in localization of the protein to the plasma membrane as part of the Wnt signaling pathway. [11]
The DUF 3608 domain sits 99 amino acids from the N-terminus and itself spans 280 amino acids. PELE predicts at least one beta sheet and two alpha helices within this domain. [12] It also contains 26 highly conserved residues and several post-translation modifications. Both occurrences are addressed later in this article.
Evidence for the function of DUF 3608 has been uncovered in the yeast homolog Iml1p. Imlp1's DUF 3608 is thought to aid in binding to two protein partners, Npr2 and Npr3. Together, these three proteins form the Iml1-Npr2-Npr3 complex and are involved in "non-nitrogen starvation" autophagy regulation. The researchers who uncovered this propose renaming DUF 3608 to RANS (Required for Autophagy induced under Non-nitrogen Starvation conditions). [13]
Based on unanimous consensus by the secondary structure prediction tool PELE, DEPDC5 contains at least ten alpha helices and nine beta sheets. The locations of these secondary structures are illustrated in the image below: red highlights are alpha helices and blue highlights are beta sheets.
Fungi are the most distantly related organisms to contain a protein orthologous to human DEPDC5, including Saccharomyces cerevisiae and Albugo laibachii . In the fungi, the protein name is Iml1p, or vacuolar membrane-associated protein Iml1. Name deviations in other organisms include CG12090 ( Drosophila ) and AGAP007010 (mosquito). [7] Conservation is high between humans and other vertebrate species, ranging from 74% identity in cichlids to 99% identity in chimpanzees. [14]
The following table summarizes an analysis of 20 proteins orthologous to human DEPDC5.
| Species | Common Name | NCBI Accession # | NCBI Name | Length | Sequence Identity | Sequence Similarity | Years Since Divergence from Human (mya) [15] |
|---|---|---|---|---|---|---|---|
| Pan troglodytes | Chimpanzee | XP_003317262 | DEPDC5 | 1572 aa | 99% | 99% | 6.4 |
| Nomascus leucogenys | Gibbon | XP_003258163 | DEPDC5 | 1602 aa | 99% | 99% | 20.4 |
| Mus musculus | Mouse | NP_001164038 | DEPDC5 | 1591 aa | 94% | 96% | 92.4 |
| Bos Taurus | Cow | XP_002694678 | DEPDC5 | 1593 aa | 94% | 96% | 94.4 |
| Sorex araneus | Shrew | ACE77702 | DEPDC5 | 1570 aa | 94% | 96% | 94.4 |
| Monodelphis domestica | Possum | XP_001378772 | DEPDC5 | 1522 aa | 89% | 93% | 163.9 |
| Gallus gallus | Chicken | XP_415249 | DEPDC5 | 1592 aa | 88% | 93% | 301.7 |
| Meleagris gallopavo | Turkey | XP_003211073 | DEPDC5 | 1592 aa | 88% | 93% | 301.7 |
| Taeniopygia guttata | Zebra finch | XP_002199825 | DEPDC5 | 1572 aa | 87% | 92% | 301.7 |
| Xenopus tropicalis | Frog | XP_002931964 | DEPDC5-like | 1574 aa | 79% | 86% | 371.2 |
| Danio rerio | Zebra fish | XP_691450 | DEPDC5-like | 1590 aa | 75% | 84% | 400.1 |
| Oreochromis niloticus | Cichlid | XP_003459226 | DEPDC5 | 1577 aa | 74% | 82% | 400.1 |
| Strongylocentrotus purpuratus | Sea urchin | XP_794020 | similar to DEPDC5 | 1608 aa | 43% | 57% | 742.9 |
| Drosophila melanogaster | Drosophila | NP_647618 | GC12090 | 1471 aa | 41% | 57% | 782.7 |
| Pediculus humanus corporis | Louse | XP_002429401 | DEPDC, putative | 1538 aa | 38% | 53% | 782.7 |
| Anopheles gambiae | Mosquito | XP_308760 | AGAP007010-PA | 1640 aa | 36% | 51% | 782.7 |
| Ascaris suum | Ascaris | ADY40551 | DEPDCp5 | 1359 aa | 31% | 51% | 937.5 |
| Ustilago maydis | Corn smut | XP_757759 | vacuolar-associated protein Iml1 | 1867 aa | 23% | 52% | 1215.8 |
| Saccharomyces cerevisiae | Yeast | NP_012672 | Iml1p | 1584 aa | 20% | 50% | 1215.8 |
| Albugo laibachii | White rust | CCA27519 | vacuolar membrane-associated protein putative | 1591 aa | 20% | 46% | 1362 |
30 residues have been conserved since animals and fungi diverged, with 26 of these located in the DUF 3608 domain. [16] The following multiple sequence alignment illustrates this conservation of the DUF domain; representatives from invertebrate and fungal clades are aligned to the human DUF 3608 with completely conserved residues colored green.
There are no known human DEPDC5 paralogs, [14] but there are 64 human proteins containing a homologous DEP domain. [17] There are also no identified paralogs for the yeast protein Iml1, the most distantly related ortholog of human DEPDC5. [14]
DEPDC5 expression has been characterized as ubiquitous in human tissue by RT-PCR analysis [18] and in DNA microarray studies as displayed in the chart below. [19] 
One study on patients with hepatocellular carcinoma found higher DEPDC5 expression in tumor tissue than in non-tumor tissue. [5] Conversely, a homozygous deletion of three genes, one being DEPDC5, was found in two glioblastoma cases. [6] Other expression anomalies include zero expression in MDA-MB-231 breast cancer cell line [20] and low expression in P116 (ZAP70 negative) cell line. [21]
The following post-translational modifications were predicted with the proteomic tools compiled at ExPASy [22] and PhosphoSite Plus [23] for the human DEPDC5 protein.
| Post-translational Modification | Number/Loci | Source |
|---|---|---|
| Phosphorylation | 133/(Ser: 87 Thr: 23 Tyr: 23) | NetPhos |
| 6/S579, S582, S1499, Y1515, Y1519, Y1543 | PhosphoSite Plus | |
| Glycation | 29/5, 8, 13, 14, 28, 34, 56, 59, 64, 93, 131, 147, 229, 247, 256, 319, 436, 528, 609, 710, 862, 878, 1008, 1185, 1233, 1387, 1408, 1499, 1567, 1597 | NetGlycate |
| N-glycosylation site | 9/N201, N298, N311, N384, N684, N1157, N1377, N1444, N1529 | NetNGlyc |
| Sulfation | 3/Y397, Y459, Y462 | Sulfinator |
| Sumoylation | 2/K59, K147 | SUMOsp Archived 2013-05-10 at the Wayback Machine |
| Propeptide cleavage | 2/R1004-M1005, R1528-N1529 | ProP |
| O-glycosylation | 0 | NetOGlyc |
| C-mannosylation | 0 | NetCGlyc |
| Myristoylation | 0 | Myristoylation |
| Prenylation | 0 | PrePS Archived 2012-02-08 at the Wayback Machine |
| Acetylation | 0 | NetAcet |
DEPDC5 may possibly interact with the proteasome subunit PSMA3 as evidenced by coimmunoprecipitation [24] and the transcription factor MYC. [25] DEPDC5 is in the "GATOR1" complex with NPRL2 and NPRL3. [26]
A leucine zipper is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine side chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.
HNF1 homeobox A, also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains a SNP associated with increased risk of coronary artery disease.
Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.
Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.
Ribonuclease 4 is an enzyme that in humans is encoded by the RNASE4 gene.
SOGA2, also known as Suppressor of glucose autophagy associated 2 or CCDC165, is a protein that in humans is encoded by the SOGA2 gene. SOGA2 has two human paralogs, SOGA1 and SOGA3. In humans, the gene coding sequence is 151,349 base pairs long, with an mRNA of 6092 base pairs, and a protein sequence of 1586 amino acids. The SOGA2 gene is conserved in gorilla, baboon, galago, rat, mouse, cat, and more. There is distant conservation seen in organisms such as zebra finches and anoles. SOGA2 is ubiquitously expressed in humans, with especially high expression in brain, colon, pituitary gland, small intestine, spinal cord, testis and fetal brain.
Basic Leucine Zipper and W2 Domain-Containing Protein 2 is a protein that is encoded by the BZW2 gene. It is a eukaryotic translation factor found in species up to bacteria. In animals, it is localized in the cytoplasm and expressed ubiquitously throughout the body. The heart, placenta, skeletal muscle, and hippocampus show higher expression. In various cancers, upregulation tends to lead to higher severity and mortality. It has been found to interact with SARS-CoV-2.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
Tetratricopeptide repeat 39A is a human protein encoded by the TTC39A gene. TTC39A is also known as DEME-6, KIAA0452, and c1orf34. The function of TTC39A is currently not well understood. The main feature within tetratricopeptide repeat 39A is the domain of unknown function 3808 (DUF3808), spanning almost the entire protein. KIAA0452 can also be seen as an isoform of TTC39A because of differences in genome sequence, but overlap in DUF domain.
Glis1 is gene encoding a Krüppel-like protein of the same name whose locus is found on Chromosome 1p32.3. The gene is enriched in unfertilised eggs and embryos at the one cell stage and it can be used to promote direct reprogramming of somatic cells to induced pluripotent stem cells, also known as iPS cells. Glis1 is a highly promiscuous transcription factor, regulating the expression of numerous genes, either positively or negatively. In organisms, Glis1 does not appear to have any directly important functions. Mice whose Glis1 gene has been removed have no noticeable change to their phenotype.
Coiled-coil domain-containing protein 144A is a protein that in humans is encoded by the CCDC144A gene. An alias of this gene is called KIAA0565. There are four members of the CCDC family: CCDC 144A, 144B, 144C and putative CCDC 144 N-terminal like proteins.
Family with sequence similarity 149, member A is a protein that in humans is encoded by the FAM149A gene. It is well conserved in primates, dog, cow, mouse, rat, and chicken. It has one paralog, FAM149B.
WW and C2 domain containing 2 (WWC2) is a protein that in humans is encoded by the WWC2 gene (4q35.1). Though function of WWC2 remains unknown, it has been predicted that WWC2 may play a role in cancer.
Family with sequence similarity 167, member A is a protein in humans that is encoded by the FAM167A gene located on chromosome 8. FAM167A and its paralogs are protein encoding genes containing the conserved domain DUF3259, a protein of unknown function. FAM167A has many orthologs in which the domain of unknown function is highly conserved.
EVI5L is a protein that in humans is encoded by the EVI5L gene. EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity. Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.
C5orf34 is a protein that in humans is encoded by the C5orf34 gene (5p12).
PROSER2, also known as proline and serine rich 2, is a protein that in humans is encoded by the PROSER2 gene. PROSER2, or c10orf47(Chromosome 10 open reading frame 47), is found in band 14 of the short arm of chromosome 10 (10p14) and contains a highly conserved SARG domain. It is a fast evolving gene with two paralogs, c1orf116 and specifically androgen-regulated gene protein isoform 1. The PROSER2 protein has a currently uncharacterized function however, in humans, it may play a role in cell cycle regulation, reproductive functioning, and is a potential biomarker of cancer.
Protein FAM208B is a protein that in humans is encoded by the FAM208B gene. The gene is also known as "chromosome 10 open reading frame 18" (c10orf18). FAM208B is expressed throughout the body however its function has not been established. FAM208b has been observed to be differentially regulated in various cancers and throughout development. While the exact role of the protein is yet to be established, the significant presence of the protein within humans and throughout the phylogenetic tree depicts a central importance of the gene in normal function.
ZNF839 or zinc finger protein 839 is a protein which in humans is encoded by the ZNF839 gene. It is located on the long arm of chromosome 14. Zinc finger protein 839 is speculated to play a role in humoral immune response to cancer as a renal carcinoma antigen (NY-REN-50). This is because NY-REN-50 was found to be over expressed in cancer patients, especially those with renal carcinoma. Zinc finger protein 839 also plays a role in transcription regulation by metal-ion binding since it binds to DNA via C2H2-type zinc finger repeats.
