DEPDC5

DEPDC5 (or DEP domain-containing 5) is a human protein of poorly understood function but has been associated with cancer in several studies. It is encoded by a gene of the same name, located on chromosome 22.

Function 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).

Mutations in this gene have been associated to cases of focal epilepsy (doi:10.1038/ng.2601).

Gene 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.

Structure

Domains

DEP The DEP domain derives its name from the proteins Dishevelled, Egl-10 and Pleckstrin, each of which contain a variant of this domain. 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.

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. 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.

DUF 3608

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. 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).

Secondary structure

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.

Homology

Orthologs 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). Conservation is high between humans and other vertebrate species, ranging from 74% identity in cichlids to 99% identity in chimpanzees.

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) Pan troglodytesChimpanzeeXP_003317262DEPDC51572 aa99%99%6.4 Nomascus leucogenysGibbonXP_003258163DEPDC51602 aa99%99%20.4 Mus musculusMouseNP_001164038DEPDC51591 aa94%96%92.4 Bos TaurusCowXP_002694678DEPDC51593 aa94%96%94.4 Sorex araneusShrewACE77702DEPDC51570 aa94%96%94.4 Monodelphis domesticaPossumXP_001378772DEPDC51522 aa89%93%163.9 Gallus gallusChickenXP_415249DEPDC51592 aa88%93%301.7 Meleagris gallopavoTurkeyXP_003211073DEPDC51592 aa88%93%301.7 Taeniopygia guttataZebra finchXP_002199825DEPDC51572 aa87%92%301.7 Xenopus tropicalisFrogXP_002931964DEPDC5-like1574 aa79%86%371.2 Danio rerioZebra fishXP_691450DEPDC5-like1590 aa75%84%400.1 Oreochromis niloticusCichlidXP_003459226DEPDC51577 aa74%82%400.1 Strongylocentrotus purpuratusSea urchinXP_794020similar to DEPDC51608 aa43%57%742.9 Drosophila melanogasterDrosophilaNP_647618GC120901471 aa41%57%782.7 Pediculus humanus corporisLouseXP_002429401DEPDC, putative1538 aa38%53%782.7 Anopheles gambiaeMosquitoXP_308760AGAP007010-PA1640 aa36%51%782.7 Ascaris suumAscarisADY40551DEPDCp51359 aa31%51%937.5 Ustilago maydisCorn smutXP_757759vacuolar-associated protein Iml11867 aa23%52%1215.8 Saccharomyces cerevisiaeYeastNP_012672Iml1p1584 aa20%50%1215.8 Albugo laibachiiWhite rustCCA27519vacuolar membrane-associated protein putative1591 aa20%46%1362 30 residues have been conserved since animals and fungi diverged, with 26 of these located in the DUF 3608 domain. 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.

Paralogs There are no known human DEPDC5 paralogs, but there are 64 human proteins containing a homologous DEP domain. There are also no identified paralogs for the yeast protein Iml1, the most distantly related ortholog of human DEPDC5.

Expression

DEPDC5 expression has been characterized as ubiquitous in human tissue by RT-PCR analysis and in DNA microarray studies as displayed in the chart below.

One study on patients with hepatocellular carcinoma found higher DEPDC5 expression in tumor tissue than in non-tumor tissue. Conversely, a homozygous deletion of three genes, one being DEPDC5, was found in two glioblastoma cases. Other expression anomalies include zero expression in MDA-MB-231 breast cancer cell line and low expression in P116 (ZAP70 negative) cell line.

Post-translational modifications The following post-translational modifications were predicted with the proteomic tools compiled at ExPASy and PhosphoSite Plus for the human DEPDC5 protein. Post-translational Modification Number/Loci Source Phosphorylation133/(Ser: 87 Thr: 23 Tyr: 23) NetPhos 6/S579, S582, S1499, Y1515, Y1519, Y1543 PhosphoSite Plus Glycation29/5, 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 site9/N201, N298, N311, N384, N684, N1157, N1377, N1444, N1529NetNGlyc Sulfation3/Y397, Y459, Y462Sulfinator Sumoylation2/K59, K147 SUMOsp Propeptide cleavage2/R1004-M1005, R1528-N1529 ProP O-glycosylation0 NetOGlyc C-mannosylation0 NetCGlyc Myristoylation0Myristoylation Prenylation0 PrePS Acetylation0 NetAcet

Interaction DEPDC5 may possibly interact with the proteasome subunit PSMA3 as evidenced by coimmunoprecipitation and the transcription factor MYC. DEPDC5 is in the "GATOR1" complex with NPRL2 and NPRL3.

References