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词条 DEPDC5
释义

  1. Function

  2. Gene

  3. Structure

     Domains  DEP  DUF 3608  Secondary Structure 

  4. Homology

     Orthologs  Paralogs 

  5. Expression

  6. Post-translational Modifications

  7. Interaction

  8. References

{{Infobox_gene}}

DEPDC5 (or DEP domain-containing 5) is a human protein of poorly understood function but has been associated with cancer in several studies.[1][2] 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).[3]

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.[1]

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.[3] 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.[4]

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.[5] 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.[6]

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.[7] 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).[8]

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).[9] Conservation is high between humans and other vertebrate species, ranging from 74% identity in cichlids to 99% identity in chimpanzees.[12]

The following table summarizes an analysis of 20 proteins orthologous to human DEPDC5.

SpeciesCommon NameNCBI Accession #NCBI NameLengthSequence IdentitySequence SimilarityYears Since Divergence from Human (mya)[10]
Pan troglodytesChimpanzee[https://www.ncbi.nlm.nih.gov/protein/XP_003317262 XP_003317262]DEPDC51572 aa99%99%6.4
Nomascus leucogenysGibbon[https://www.ncbi.nlm.nih.gov/protein/XP_003258163 XP_003258163]DEPDC51602 aa99%99%20.4
Mus musculusMouse[https://www.ncbi.nlm.nih.gov/protein/NP_001164038 NP_001164038]DEPDC51591 aa94%96%92.4
Bos TaurusCow[https://www.ncbi.nlm.nih.gov/protein/XP_002694678 XP_002694678]DEPDC51593 aa94%96%94.4
Sorex araneusShrew[https://www.ncbi.nlm.nih.gov/protein/ACE77702 ACE77702]DEPDC51570 aa94%96%94.4
Monodelphis domesticaPossum[https://www.ncbi.nlm.nih.gov/protein/XP_001378772 XP_001378772]DEPDC51522 aa89%93%163.9
Gallus gallusChicken[https://www.ncbi.nlm.nih.gov/protein/XP_415249 XP_415249]DEPDC51592 aa88%93%301.7
Meleagris gallopavoTurkey[https://www.ncbi.nlm.nih.gov/protein/XP_003211073 XP_003211073]DEPDC51592 aa88%93%301.7
Taeniopygia guttataZebra finch[https://www.ncbi.nlm.nih.gov/protein/XP_002199825 XP_002199825]DEPDC51572 aa87%92%301.7
Xenopus tropicalisFrog[https://www.ncbi.nlm.nih.gov/protein/XP_002931964 XP_002931964]DEPDC5-like1574 aa79%86%371.2
Danio rerioZebra fish[https://www.ncbi.nlm.nih.gov/protein/XP_691450 XP_691450]DEPDC5-like1590 aa75%84%400.1
Oreochromis niloticusCichlid[https://www.ncbi.nlm.nih.gov/protein/XP_003459226 XP_003459226]DEPDC51577 aa74%82%400.1
Strongylocentrotus purpuratusSea urchin[https://www.ncbi.nlm.nih.gov/protein/XP_794020 XP_794020]similar to DEPDC51608 aa43%57%742.9
Drosophila melanogasterDrosophila[https://www.ncbi.nlm.nih.gov/protein/NP_647618 NP_647618]GC120901471 aa41%57%782.7
Pediculus humanus corporisLouse[https://www.ncbi.nlm.nih.gov/protein/XP_002429401 XP_002429401]DEPDC, putative1538 aa38%53%782.7
Anopheles gambiaeMosquito[https://www.ncbi.nlm.nih.gov/protein/XP_308760 XP_308760]AGAP007010-PA1640 aa36%51%782.7
Ascaris suumAscaris[https://www.ncbi.nlm.nih.gov/protein/ADY40551 ADY40551]DEPDCp51359 aa31%51%937.5
Ustilago maydisCorn smut[https://www.ncbi.nlm.nih.gov/protein/XP_757759 XP_757759]vacuolar-associated protein Iml11867 aa23%52%1215.8
Saccharomyces cerevisiaeYeast[https://www.ncbi.nlm.nih.gov/protein/NP_012672 NP_012672]Iml1p1584 aa20%50%1215.8
Albugo laibachiiWhite rust[https://www.ncbi.nlm.nih.gov/protein/CCA27519 CCA27519]vacuolar 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.[11] 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,[12] but there are 64 human proteins containing a homologous DEP domain.[13] There are also no identified paralogs for the yeast protein Iml1, the most distantly related ortholog of human DEPDC5.[12]

Expression

DEPDC5 expression has been characterized as ubiquitous in human tissue by RT-PCR analysis[14] and in DNA microarray studies as displayed in the chart below.[15]

One study on patients with hepatocellular carcinoma found higher DEPDC5 expression in tumor tissue than in non-tumor tissue.[1] Conversely, a homozygous deletion of three genes, one being DEPDC5, was found in two glioblastoma cases.[2] Other expression anomalies include zero expression in MDA-MB-231 breast cancer cell line[16] and low expression in P116 (ZAP70 negative) cell line.[17]

Post-translational Modifications

The following post-translational modifications were predicted with the proteomic tools compiled at ExPASy[18] and PhosphoSite Plus[19] for the human DEPDC5 protein.

Post-translational ModificationNumber/LociSource
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[20] and the transcription factor MYC.[21] DEPDC5 is in the "GATOR1" complex with NPRL2 and NPRL3.[22]

References

1. ^1 2 {{cite journal |vauthors=Miki D, Ochi H, Hayes CN |title=Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers |journal=Nat. Genet. |volume=43 |issue=8 |pages=797–800 |date=August 2011 |pmid=21725309 |doi=10.1038/ng.876 |url=|display-authors=etal}}
2. ^1 {{cite journal |vauthors=Seng TJ, Ichimura K, Liu L, Tingby O, Pearson DM, Collins VP |title=Complex chromosome 22 rearrangements in astrocytic tumors identified using microsatellite and chromosome 22 tile path array analysis |journal=Genes Chromosomes Cancer |volume=43 |issue=2 |pages=181–93 |date=June 2005 |pmid=15770670 |doi=10.1002/gcc.20181 |url=}}
3. ^{{cite web|title=AceView: Homo sapiens complex locus DEPDC5, encoding DEP domain containing 5|url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=DEPDC5&submit=Go}}
4. ^{{cite web|title=SWISS-MODEL|url=http://swissmodel.expasy.org/}}
5. ^{{cite web|title=NCBI: CBLAST|url=https://www.ncbi.nlm.nih.gov/Structure/cblast/cblast.cgi}}
6. ^{{cite journal |vauthors=Pan WJ, Pang SZ, Huang T, Guo HY, Wu D, Li L |title=Characterization of function of three domains in dishevelled-1: DEP domain is responsible for membrane translocation of dishevelled-1 |journal=Cell Res. |volume=14 |issue=4 |pages=324–30 |date=August 2004 |pmid=15353129 |doi=10.1038/sj.cr.7290232 |url=}}
7. ^{{cite web|title=Biology Workbench: PELE|url=http://workbench.sdsc.edu/}}
8. ^{{cite journal |vauthors=Wu X, Tu BP |title=Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation |journal=Mol. Biol. Cell |volume=22 |issue=21 |pages=4124–33 |date=November 2011 |pmid=21900499 |pmc=3204073 |doi=10.1091/mbc.E11-06-0525 |url=}}
9. ^1 {{cite web|title=GeneCards: DEP domain containing 5|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=DEPDC5&search=DEPDc5}}
10. ^{{cite web|title=TimeTree|url=http://timetree.org/}}
11. ^{{cite web|title=Biology Workbench: ClustalW|url=http://workbench.sdsc.edu/}}
12. ^1 2 {{cite web|title=NCBI|url=http://blast.ncbi.nlm.nih.gov/Blast.cgi}}
13. ^{{cite journal |vauthors=Civera C, Simon B, Stier G, Sattler M, Macias MJ |title=Structure and dynamics of the human pleckstrin DEP domain: distinct molecular features of a novel DEP domain subfamily |journal=Proteins |volume=58 |issue=2 |pages=354–66 |date=February 2005 |pmid=15573383 |doi=10.1002/prot.20320 |url=}}
14. ^{{cite journal |vauthors=Ishikawa K, Nagase T, Suyama M |title=Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro |journal=DNA Res. |volume=5 |issue=3 |pages=169–76 |date=June 1998 |pmid=9734811 |doi= 10.1093/dnares/5.3.169|url=|display-authors=etal}}
15. ^{{cite journal |vauthors=Johnson JM, Castle J, Garrett-Engele P |title=Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays |journal=Science |volume=302 |issue=5653 |pages=2141–4 |date=December 2003 |pmid=14684825 |doi=10.1126/science.1090100 |url=|display-authors=etal}}
16. ^{{cite journal |vauthors=Cappellen D, Schlange T, Bauer M, Maurer F, Hynes NE |title=Novel c-MYC target genes mediate differential effects on cell proliferation and migration |journal=EMBO Rep. |volume=8 |issue=1 |pages=70–6 |date=January 2007 |pmid=17159920 |pmc=1796762 |doi=10.1038/sj.embor.7400849 |url=}}
17. ^{{cite journal |vauthors=Roose JP, Diehn M, Tomlinson MG |title=T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression |journal=PLoS Biol. |volume=1 |issue=2 |pages=E53 |date=November 2003 |pmid=14624253 |pmc=261890 |doi=10.1371/journal.pbio.0000053 |url=|display-authors=etal}} {{open access}}
18. ^{{cite web|title=ExPASy Proteomic Tools: Post-translational modification prediction|url=http://expasy.org/tools/#ptm}}
19. ^{{cite web|title=PhosphoSite Plus: DEPDC5|url=http://www.phosphosite.org/proteinAction.do?id=14476&showAllSites=true}}
20. ^{{cite journal |vauthors=Lim J, Hao T, Shaw C |title=A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration |journal=Cell |volume=125 |issue=4 |pages=801–14 |date=May 2006 |pmid=16713569 |doi=10.1016/j.cell.2006.03.032 |url=|display-authors=etal}}
21. ^{{cite journal |vauthors=Zeller KI, Zhao X, Lee CW |title=Global mapping of c-Myc binding sites and target gene networks in human B cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=47 |pages=17834–9 |date=November 2006 |pmid=17093053 |pmc=1635161 |doi=10.1073/pnas.0604129103 |url=|display-authors=etal}}
22. ^{{Cite journal | pmid = 23723238| pmc = 3728654| year = 2013| author1 = Bar-Peled| first1 = L| title = A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1| journal = Science| volume = 340| issue = 6136| pages = 1100–6| last2 = Chantranupong| first2 = L| last3 = Cherniack| first3 = A. D.| last4 = Chen| first4 = W. W.| last5 = Ottina| first5 = K. A.| last6 = Grabiner| first6 = B. C.| last7 = Spear| first7 = E. D.| last8 = Carter| first8 = S. L.| last9 = Meyerson| first9 = M| last10 = Sabatini| first10 = D. M.| doi = 10.1126/science.1232044}}
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