DEPDC5

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

Function
The function of DEPDC5 is not yet known, but it has been implicated in intracellular is_associated_with::signal transduction based on homology between the DEP domains of DEPDC5 and Dishevelled-1 (is_associated_with::DVL1).

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

Gene
In is_associated_with::Homo sapiens, the DEPDC5 gene has been localized to the long arm of chromosome 22, 22q12.2-q12.3, between the is_associated_with::PRRL14 and is_associated_with::YWHAH genes. The clinical relevance of this gene includes an intronic SNP (rs1012068) that has been associated with a 2-fold is_associated_with::hepatocellular carcinoma-risk increase.

DEP
The is_associated_with::DEP domain derives its name from the proteins is_associated_with::Dishevelled, is_associated_with::Egl-10 and is_associated_with::Pleckstrin, each of which contain a variant of this domain. It spans 82 residues and is 343 is_associated_with::amino acids from the is_associated_with::C-terminus. A is_associated_with::SWISS-MODEL predicts two is_associated_with::beta sheets and three is_associated_with::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 is_associated_with::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 is_associated_with::plasma membrane as part of the is_associated_with::Wnt signaling pathway.

DUF 3608
The DUF 3608 domain sits 99 amino acids from the is_associated_with::N-terminus and itself spans 280 amino acids. is_associated_with::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 is_associated_with::yeast homolog is_associated_with::Iml1p. Imlp1's DUF 3608 is thought to aid in binding to two protein partners, is_associated_with::Npr2 and is_associated_with::Npr3. Together, these three proteins form the Iml1-Npr2-Npr3 complex and are involved in "non-nitrogen starvation" is_associated_with::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.

Orthologs
is_associated_with::Fungi are the most distantly related organisms to contain a protein is_associated_with::orthologous to human DEPDC5, including is_associated_with::Saccharomyces cerevisiae and is_associated_with::Albugo is_associated_with::laibachii. In the fungi, the protein name is is_associated_with::Iml1p, or vacuolar membrane-associated protein Iml1. Name deviations in other organisms include is_associated_with::CG12090 (is_associated_with::Drosophila) and is_associated_with::AGAP007010 (is_associated_with::mosquito). Conservation is high between humans and other is_associated_with::vertebrate species, ranging from 74% identity in is_associated_with::cichlids to 99% identity in is_associated_with::chimpanzees.

The following table summarizes an analysis of 20 proteins orthologous to human DEPDC5. 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 is_associated_with::invertebrate and fungal is_associated_with::clades are aligned to the human DUF 3608 with completely conserved residues colored green.

Paralogs
There are no known human DEPDC5 is_associated_with::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 is_associated_with::RT-PCR analysis and in is_associated_with::DNA microarray studies as displayed in the chart below.

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

Post-translational Modifications
The following is_associated_with::post-translational modifications were predicted with the proteomic tools compiled at is_associated_with::ExPASy and is_associated_with::PhosphoSite Plus for the human DEPDC5 protein.

Interaction
DEPDC5 may possibly interact with the is_associated_with::proteasome subunit is_associated_with::PSMA3 as evidenced by is_associated_with::coimmunoprecipitation and the transcription factor is_associated_with::MYC. DEPDC5 is in the "GATOR1" complex with is_associated_with::Nprl2 and is_associated_with::Nprl3.