DAP3

28S ribosomal protein S29, mitochondrial, also known as death-associated protein 3 (DAP3), is a protein that in humans is encoded by the DAP3 gene on chromosome 1.[5][6][7][8] This gene encodes a 28S subunit protein of the mitochondrial ribosome (mitoribosome) and plays key roles in translation, cellular respiration, and apoptosis.[7][8][9][10] Moreover, DAP3 is associated with cancer development, but has been observed to aid some cancers while suppressing others.[10][11][12]

DAP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3J9M
Identifiers
Aliases	DAP3, DAP-3, MRP-S29, MRPS29, bMRP-10, death associated protein 3, S29mt
External IDs	OMIM: 602074 MGI: 1929538 HomoloGene: 3404 GeneCards: DAP3
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q22 Start 155,687,960 bp[1] End 155,739,010 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 F1|3 39.01 cM Start 88,920,803 bp[2] End 88,951,181 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • structural constituent of ribosome • GO:0001948 protein binding • RNA binding • nucleotide binding • GTP binding Cellular component • small ribosomal subunit • mitochondrial inner membrane • ribosome • mitochondrial ribosome • mitochondrion • mitochondrial small ribosomal subunit • nucleoplasm Biological process • apoptotic signaling pathway • mitochondrial translational elongation • mitochondrial translational termination • apoptotic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7818	65111
Ensembl	ENSG00000132676	ENSMUSG00000068921
UniProt	P51398	Q9ER88
RefSeq (mRNA)	NM_001199849 NM_001199850 NM_001199851 NM_004632 NM_033657	NM_001164533 NM_022994 NM_001368419
RefSeq (protein)	NP_001186778 NP_001186779 NP_001186780 NP_004623 NP_387506	NP_001158005 NP_075370 NP_001355348
Location (UCSC)	Chr 1: 155.69 – 155.74 Mb	Chr 3: 88.92 – 88.95 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The DAP3 gene encodes a 46 kDa protein located in the lower area of the small mitoribosomal subunit.[9][12][13][14] This protein contains a P-loop motif that binds GTP and a highly conserved 17-residue targeting sequence responsible for its localization to the mitochondria.[9][11][12][13] Of interest, many of the phosphorylation sites on this protein are highly conserved and clustered around GTP-binding motifs.[9]

Several splice variants were observed in human ESTs that differ largely in the 5’ UTR region.[7][14] Pseudogenes for this gene are also found in chromosomes 1 and 2.[7]

Function

DAP3 is a 28S subunit protein of mitoribosomes and localizes to the mitochondrial matrix.[7][8][9] As part of the mitoribosome, DAP3 participates in the translation of the 13 ETC complex proteins encoded in the mitochondrial genome, and consequently, in the regulation of cellular respiration.[7][8][9][10] As a member of the death-associated protein (DAP) family, DAP3 can also be found outside of the mitochondria to initiate the extrinsic apoptotic pathway through its interactions with apoptotic factors, such as tumor necrosis factor-alpha, Fas ligand, and gamma interferon.[7][8][11][12][13] Additionally, DAP3 interacts with the factor IPS-1 to activate caspases 3, 8, and 9, resulting in a type of extracellular apoptosis called anoikis.[12][13] Moreover, DAP3 may contribute to apoptosis through its mediation of mitochondrial fragmentation, as this function extends to the mediation of the oxidative stress response, reactive oxygen species (ROS) production, and ultimately, mitochondrial homeostasis.[10][11][13] DAP3 is essential for life, and its deletion in embryos is lethal.[14] Nonetheless, DAP3 and its apoptotic activity can be inhibited by AKT phosphorylation.[12][13]

Clinical significance

As aforementioned, death associated protein 3 (DAP3) has regulatory roles in cell respiration and apoptosis. Both opposites and cell respiration are important elements of cell death pathways and have underlying mechanistic roles in ischemia-reperfusion injury.[15][16][17]

During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[18] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.

DAP3 has been implicated in numerous cancers. Studies demonstrated that DAP3 expression tended to be low to nonexistent in the tumor cells of B-cell lymphoma, non-small cell lung cancer, head and neck cancer, breast cancer, gastric cancer, and colon cancer, possibly due to hypermethylation of the gene’s promoter.[11][12] Moreover, DAP3 expression has been positively correlated with improved cancer prognosis, indicating that the protein combats cancer progression through its proapoptotic function.[11][12] As a result, DAP3 could serve as a potential biomarker to monitor the effectiveness of therapeutic treatments such as chemotherapy.[11] However, in other cancers, such as glioblastoma multiforme (GBM) and thymoma, DAP3 expression was found to be upregulated.[10][14] Thus, the specific role of DAP3 in various cancers requires further study.[17]

Interactions

DAP3 has been shown to interact with:

• DELE,[12]
• IPS-1,[12]
• AKT,[12]
• PKA,[14]
• PKC,[14]
• NOA1,[8][14]
• FADD,[19]
• Glucocorticoid receptor,[20]
• Heat shock protein 90kDa alpha (cytosolic), member A1,[20] and
• TNFRSF10A.[19]

References

1. GRCh38: Ensembl release 89: ENSG00000132676 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000068921 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kissil JL, Deiss LP, Bayewitch M, Raveh T, Khaspekov G, Kimchi A (Nov 1995). "Isolation of DAP3, a novel mediator of interferon-gamma-induced cell death". The Journal of Biological Chemistry. 270 (46): 27932–6. doi:10.1074/jbc.270.46.27932. PMID 7499268.
6. Kissil JL, Kimchi A (September 1997). "Assignment of death associated protein 3 (DAP3) to human chromosome 1q21 by in situ hybridization". Cytogenetics and Cell Genetics. 77 (3–4): 252. doi:10.1159/000134587. PMID 9284927.
7. "Entrez Gene: DAP3 death associated protein 3".
8. Tang T, Zheng B, Chen SH, Murphy AN, Kudlicka K, Zhou H, Farquhar MG (Feb 2009). "hNOA1 interacts with complex I and DAP3 and regulates mitochondrial respiration and apoptosis". The Journal of Biological Chemistry. 284 (8): 5414–24. doi:10.1074/jbc.M807797200. PMC 2643507. PMID 19103604.
9. Miller JL, Koc H, Koc EC (Feb 2008). "Identification of phosphorylation sites in mammalian mitochondrial ribosomal protein DAP3". Protein Science. 17 (2): 251–60. doi:10.1110/ps.073185608. PMC 2222727. PMID 18227431.
10. Jacques C, Fontaine JF, Franc B, Mirebeau-Prunier D, Triau S, Savagner F, Malthiery Y (Jul 2009). "Death-associated protein 3 is overexpressed in human thyroid oncocytic tumours". British Journal of Cancer. 101 (1): 132–8. doi:10.1038/sj.bjc.6605111. PMC 2713694. PMID 19536094.
11. Jia Y, Ye L, Ji K, Zhang L, Hargest R, Ji J, Jiang WG (Jan 2014). "Death-associated protein-3, DAP-3, correlates with preoperative chemotherapy effectiveness and prognosis of gastric cancer patients following perioperative chemotherapy and radical gastrectomy". British Journal of Cancer. 110 (2): 421–9. doi:10.1038/bjc.2013.712. PMC 3899757. PMID 24300973.
12. Wazir U, Jiang WG, Sharma AK, Mokbel K (Feb 2012). "The mRNA expression of DAP3 in human breast cancer: correlation with clinicopathological parameters". Anticancer Research. 32 (2): 671–4. PMID 22287761.
13. Miyazaki T, Shen M, Fujikura D, Tosa N, Kim HR, Kon S, Uede T, Reed JC (Oct 2004). "Functional role of death-associated protein 3 (DAP3) in anoikis". The Journal of Biological Chemistry. 279 (43): 44667–72. doi:10.1074/jbc.M408101200. PMID 15302871.
14. Han MJ, Chiu DT, Koc EC (Apr 2010). "Regulation of mitochondrial ribosomal protein S29 (MRPS29) expression by a 5'-upstream open reading frame". Mitochondrion. 10 (3): 274–83. doi:10.1016/j.mito.2009.12.150. PMC 2844934. PMID 20079882.
15. Gracia-Sancho J, Casillas-Ramírez A, Peralta C (Aug 2015). "Molecular pathways in protecting the liver from ischaemia/reperfusion injury: a 2015 update". Clinical Science. 129 (4): 345–62. doi:10.1042/CS20150223. PMID 26014222.
16. Ekert PG, Vaux DL (Dec 2005). "The mitochondrial death squad: hardened killers or innocent bystanders?". Current Opinion in Cell Biology. 17 (6): 626–30. doi:10.1016/j.ceb.2005.09.001. PMID 16219456.
17. Kissil JL, Kimchi A (Jun 1998). "Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions". Molecular Medicine Today. 4 (6): 268–74. doi:10.1016/s1357-4310(98)01263-5. PMID 9679246.
18. Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.
19. Miyazaki T, Reed JC (Jun 2001). "A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins". Nature Immunology. 2 (6): 493–500. doi:10.1038/88684. PMID 11376335.
20. Hulkko SM, Wakui H, Zilliacus J (Aug 2000). "The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function". The Biochemical Journal. 349 (3): 885–93. doi:10.1042/bj3490885. PMC 1221218. PMID 10903152.

Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Hulkko SM, Wakui H, Zilliacus J (2000). "The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function". Biochem. J. 349 (Pt 3): 885–93. doi:10.1042/bj3490885. PMC 1221218. PMID 10903152.
• Morgan CJ, Jacques C, Savagner F, Tourmen Y, Mirebeau DP, Malthièry Y, Reynier P (2001). "A conserved N-terminal sequence targets human DAP3 to mitochondria". Biochem. Biophys. Res. Commun. 280 (1): 177–81. doi:10.1006/bbrc.2000.4119. PMID 11162496.
• Cavdar Koc E, Ranasinghe A, Burkhart W, Blackburn K, Koc H, Moseley A, Spremulli LL (2001). "A new face on apoptosis: death-associated protein 3 and PDCD9 are mitochondrial ribosomal proteins". FEBS Lett. 492 (1–2): 166–70. doi:10.1016/S0014-5793(01)02250-5. PMID 11248257.
• Cavdar Koc E, Burkhart W, Blackburn K, Moseley A, Spremulli LL (2001). "The small subunit of the mammalian mitochondrial ribosome. Identification of the full complement of ribosomal proteins present". J. Biol. Chem. 276 (22): 19363–74. doi:10.1074/jbc.M100727200. PMID 11279123.
• Miyazaki T, Reed JC (2001). "A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins". Nat. Immunol. 2 (6): 493–500. doi:10.1038/88684. PMID 11376335.
• Suzuki T, Terasaki M, Takemoto-Hori C, Hanada T, Ueda T, Wada A, Watanabe K (2001). "Proteomic analysis of the mammalian mitochondrial ribosome. Identification of protein components in the 28 S small subunit". J. Biol. Chem. 276 (35): 33181–95. doi:10.1074/jbc.M103236200. PMID 11402041.
• Kenmochi N, Suzuki T, Uechi T, Magoori M, Kuniba M, Higa S, Watanabe K, Tanaka T (2001). "The human mitochondrial ribosomal protein genes: mapping of 54 genes to the chromosomes and implications for human disorders". Genomics. 77 (1–2): 65–70. doi:10.1006/geno.2001.6622. PMID 11543634.
• Berger T, Kretzler M (2002). "Interaction of DAP3 and FADD only after cellular disruption". Nat. Immunol. 3 (1): 3–5. doi:10.1038/ni0102-3b. PMID 11753396.
• Hulkko SM, Zilliacus J (2002). "Functional interaction between the pro-apoptotic DAP3 and the glucocorticoid receptor". Biochem. Biophys. Res. Commun. 295 (3): 749–55. doi:10.1016/S0006-291X(02)00713-1. PMID 12099703.
• Berger T, Kretzler M (2002). "TRAIL-induced apoptosis is independent of the mitochondrial apoptosis mediator DAP3". Biochem. Biophys. Res. Commun. 297 (4): 880–4. doi:10.1016/S0006-291X(02)02310-0. PMID 12359235.
• Zhang Z, Gerstein M (2003). "Identification and characterization of over 100 mitochondrial ribosomal protein pseudogenes in the human genome". Genomics. 81 (5): 468–80. doi:10.1016/S0888-7543(03)00004-1. PMID 12706105.
• Mukamel Z, Kimchi A (2004). "Death-associated protein 3 localizes to the mitochondria and is involved in the process of mitochondrial fragmentation during cell death". J. Biol. Chem. 279 (35): 36732–8. doi:10.1074/jbc.M400041200. PMID 15175341.
• Hirota T, Obara K, Matsuda A, Akahoshi M, Nakashima K, Hasegawa K, Takahashi N, Shimizu M, Sekiguchi H, Kokubo M, Doi S, Fujiwara H, Miyatake A, Fujita K, Enomoto T, Kishi F, Suzuki Y, Saito H, Nakamura Y, Shirakawa T, Tamari M (2004). "Association between genetic variation in the gene for death-associated protein-3 (DAP3) and adult asthma". J. Hum. Genet. 49 (7): 370–5. doi:10.1007/s10038-004-0161-4. PMID 15179560.
• Miyazaki T, Shen M, Fujikura D, Tosa N, Kim HR, Kon S, Uede T, Reed JC (2004). "Functional role of death-associated protein 3 (DAP3) in anoikis". J. Biol. Chem. 279 (43): 44667–72. doi:10.1074/jbc.M408101200. PMID 15302871.
• Sasaki H, Ide N, Yukiue H, Kobayashi Y, Fukai I, Yamakawa Y, Fujii Y (2004). "Arg and DAP3 expression was correlated with human thymoma stage". Clin. Exp. Metastasis. 21 (6): 507–13. doi:10.1007/s10585-004-2153-3. PMID 15679048.

External links

• PDBe-KB provides an overview of all the structure information available in the PDB for Human 28S ribosomal protein S29, mitochondrial (DAP3)