DNAJA3

Last updated
DNAJA3
Protein DNAJA3 PDB 2ctt.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DNAJA3 , HCA57, TID1, hTID-1, DnaJ heat shock protein family (Hsp40) member A3
External IDs OMIM: 608382; MGI: 1933786; HomoloGene: 36170; GeneCards: DNAJA3; OMA:DNAJA3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005147
NM_001135110
NM_001286516

NM_001135112
NM_023646

RefSeq (protein)

NP_001128582
NP_001273445
NP_005138
NP_005138.3

NP_001128584
NP_076135

Location (UCSC) Chr 16: 4.43 – 4.46 Mb Chr 16: 4.46 – 4.53 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. [5] [6] [7] This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. [6] [7] [8] As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. [6] [7] [9] [10] [11] Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers. [7] [9] [11] [12]

Contents

Structure

As a member of the DNAJ/Hsp40 protein family, DNAJA3 contains a conserved DnaJ domain, which includes an HPD motif that interacts with Hsp70 to perform its cochaperone function. [6] [7] [8] [9] [10] The DnaJ domain is composed of tetrahelical regions containing a tripeptide of histidine, proline and aspartic acid situated between two helices. In addition, this protein contains a glycine/phenylalanine (G/F) rich linker region and a central cysteine-rich region similar to a zinc finger repeat, both characteristic of type I DnaJ molecular chaperones. [8] [9] [10] The mitochondrial targeting sequence at its N-terminal directs the localization of the protein to the mitochondrial matrix. [8] [9] [10]

DNAJA3 possesses two alternatively spliced forms: a long isoform of 43 kDa and a short isoform of 40 kDa. [6] [7] [9] [12] The long isoform contains an additional 33 residues at its C-terminal compared to the short isoform, and this region is predicted to hinder the long isoform from regulating membrane potential. [7]

Function

DNAJA3 is a member of the DNAJ/Hsp40 protein family, which stimulates the ATPase activity of Hsp70 chaperones and plays critical roles in protein folding, degradation, and multiprotein complex assembly. [6] [7] [8] DNAJA3 localizes to the mitochondria, where it interacts with the mitochondrial Hsp70 chaperone (mtHsp70) to carry out the chaperone system. [6] [7] This protein is crucial for maintaining a homogeneous distribution of mitochondrial membrane potential and the integrity of mtDNA. DNAJA3 homogenizes membrane potential through regulation of complex I aggregation, though the mechanism for maintaining mtDNA remains unknown. [7] These functions then allow DNAJA3 to mediate mitochondrial fission through DRP1 and, by extension, cellular processes such as cell movement, growth, proliferation, differentiation, senescence, and apoptosis. [6] [7] [9] [10] [11] However, though both isoforms of DNAJA3 are involved with cell survival, they are also observed to influence two opposing outcomes. The proapoptotic long isoform induces apoptosis by stimulating cytochrome C release and caspase activation in the mitochondria, whereas the antiapoptotic short isoform prevents cytochrome C release and, thus, apoptosis. [7] [11] In neuromuscular junctions, only the short isoform clusters acetylcholine receptors for efficient synaptic transmission. [7] The two isoforms also differ in their specific mitochondrial localization, which may partially account for their different functions. [7] [11]

Before localization to the mitochondria, DNAJA3 is transiently retained in the cytosol, where it can also interact with cytosolic proteins and possibly function to transport these proteins. [8] [11]

Clinical significance

This protein is implicated in several cancers, including skin cancer, breast cancer, and colorectal cancer. [12] It is a key player in tumor suppression through interactions with oncogenic proteins, including ErbB2 and the p53 tumor suppressor protein. [6] [8] Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 through ubiquitin ligases like MDM2. Moreover, both p53 and DNAJA3 must be present in the mitochondria in order to induce apoptosis in the cell. [8] In head and neck squamous cell carcinoma (HNSCC) cancer, DNAJA3 suppresses cell proliferation, anchorage-independent growth, cell motility, and cell invasion by attenuating EGFR and, downstream the signaling pathway, AKT. [12] Thus, treatments promoting DNAJA3 expression and function may greatly aid the elimination of tumors. [8]

Additionally, DNAJA3 is implicated in neurodegenerative diseases like Parkinson's disease by virtue of its key roles in chaperoning mitochondrial proteins and mediating mitochondrial morphology in conjunction with mtHsp70. [7] [9] Another disease, psoriasis, is a chronic inflammatory skin disease that results from the absence of DNAJA3 activity, which then results in the activation of MK5, increased phosphorylation of HSP27, increased actin cytoskeleton organization, and hyperthickened skin. [11]

Interactions

DNAJA3 has been shown to interact with:

Related Research Articles

p53 Mammalian protein found in humans

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">HSPA8</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">HSPA1A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">HSPA1B</span> Human gene

Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.

<span class="mw-page-title-main">BAG1</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.

<span class="mw-page-title-main">IRF1</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 1 is a protein that in humans is encoded by the IRF1 gene.

<span class="mw-page-title-main">ING1</span> Protein-coding gene in the species Homo sapiens

Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.

<span class="mw-page-title-main">TP53BP2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">DNAJB1</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.

<span class="mw-page-title-main">ST13</span>

Hsc70-interacting protein also known as suppression of tumorigenicity 13 (ST13) is a protein that in humans is encoded by the ST13 gene.

<span class="mw-page-title-main">DNAJA1</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily A member 1 is a protein that in humans is encoded by the DNAJA1 gene.

<span class="mw-page-title-main">DNAJB6</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily B member 6 is a protein that in humans is encoded by the DNAJB6 gene.

<span class="mw-page-title-main">SIVA1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CDC14A</span> Protein-coding gene in the species Homo sapiens

Dual specificity protein phosphatase CDC14A is an enzyme that in humans is encoded by the CDC14A gene.

<span class="mw-page-title-main">DNAJA2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">BAG4</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TP53I3</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">DNAJB4</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily B member 4 is a protein that in humans is encoded by the DNAJB4 gene.

References

  1. 1 2 3 ENSG00000103423 GRCh38: Ensembl release 89: ENSG00000276726, ENSG00000103423 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000004069 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. Schilling B, De-Medina T, Syken J, Vidal M, Munger K (August 1998). "A novel human DnaJ protein, hTid-1, a homolog of the Drosophila tumor suppressor protein Tid56, can interact with the human papillomavirus type 16 E7 oncoprotein". Virology. 247 (1): 74–85. doi: 10.1006/viro.1998.9220 . PMID   9683573.
  6. 1 2 3 4 5 6 7 8 9 "Entrez Gene: DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3".
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ng, AC; Baird, SD; Screaton, RA (April 2014). "Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity". Molecular and Cellular Biology. 34 (8): 1427–37. doi:10.1128/mcb.01021-13. PMC   3993590 . PMID   24492964.
  8. 1 2 3 4 5 6 7 8 9 Ahn, BY; Trinh, DL; Zajchowski, LD; Lee, B; Elwi, AN; Kim, SW (25 February 2010). "Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer". Oncogene. 29 (8): 1155–66. doi: 10.1038/onc.2009.413 . PMID   19935715.
  9. 1 2 3 4 5 6 7 8 Elwi, AN; Lee, B; Meijndert, HC; Braun, JE; Kim, SW (August 2012). "Mitochondrial chaperone DnaJA3 induces Drp1-dependent mitochondrial fragmentation". The International Journal of Biochemistry & Cell Biology. 44 (8): 1366–76. doi:10.1016/j.biocel.2012.05.004. PMID   22595283.
  10. 1 2 3 4 5 6 Trinh, DL; Elwi, AN; Kim, SW (October 2010). "Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis". Oncotarget. 1 (6): 396–404. doi:10.18632/oncotarget.100902 (inactive 2024-09-12). PMC   3248115 . PMID   21311096.{{cite journal}}: CS1 maint: DOI inactive as of September 2024 (link)
  11. 1 2 3 4 5 6 7 8 Choi, JH; Choi, DK; Sohn, KC; Kwak, SS; Suk, J; Lim, JS; Shin, I; Kim, SW; Lee, JH; Joe, CO (27 July 2012). "Absence of a human DnaJ protein hTid-1S correlates with aberrant actin cytoskeleton organization in lesional psoriatic skin". The Journal of Biological Chemistry. 287 (31): 25954–63. doi: 10.1074/jbc.m111.313809 . PMC   3406679 . PMID   22692211.
  12. 1 2 3 4 Chen, CY; Chiou, SH; Huang, CY; Jan, CI; Lin, SC; Hu, WY; Chou, SH; Liu, CJ; Lo, JF (November 2009). "Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma". The Journal of Pathology. 219 (3): 347–55. doi:10.1002/path.2604. PMID   19681071. S2CID   23405415.
  13. 1 2 Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S (December 2001). "hTid-1, a human DnaJ protein, modulates the interferon signaling pathway". J. Biol. Chem. 276 (52): 49034–42. doi: 10.1074/jbc.M103683200 . PMID   11679576.
  14. Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M (April 2001). "A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein". J. Biol. Chem. 276 (16): 13087–95. doi: 10.1074/jbc.M009267200 . PMID   11116152.

Further reading