As a member of the DNAJ/Hsp40 protein family, DNAJA3 contains a conserved DnaJ domain, which includes an HPD motif that interacts withHsp70 to perform itscochaperone 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 azinc finger repeat, both characteristic of type I DnaJ molecular chaperones.[8][9][10] Themitochondrial targeting sequence at its N-terminal directs the localization of the protein to themitochondrial matrix.[8][9][10]
DNAJA3 possesses twoalternatively spliced forms: a longisoform 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]
DNAJA3 is a member of the DNAJ/Hsp40 protein family, which stimulates the ATPase activity of Hsp70 chaperones and plays critical roles inprotein folding,degradation, andmultiprotein complex assembly.[6][7][8] DNAJA3localizes 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 mediatemitochondrial fission throughDRP1 and, by extension, cellular processes such as cellmovement,growth, proliferation,differentiation,senescence, andapoptosis.[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 stimulatingcytochrome C release andcaspase activation in the mitochondria, whereas the antiapoptotic short isoform prevents cytochrome C release and, thus, apoptosis.[7][11] Inneuromuscular junctions, only the short isoform clustersacetylcholine receptors for efficientsynaptic 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 withcytosolic proteins and possibly function totransport these proteins.[8][11]
This protein is implicated in several cancers, includingskin cancer,breast cancer, andcolorectal cancer.[12] It is a key player in tumor suppression through interactions withoncogenic proteins, includingErbB2 and thep53 tumor suppressor protein.[6][8] Under hypoxic conditions, DNAJA3 may directly influence p53 complex assembly or modification, or indirectly ubiquitinylate p53 throughubiquitin ligases likeMDM2. 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 attenuatingEGFR 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 likeParkinson'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 achronicinflammatory skin disease that results from the absence of DNAJA3 activity, which then results in the activation ofMK5, increasedphosphorylation ofHSP27, increasedactincytoskeleton organization, and hyperthickened skin.[11]
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.PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (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.PMID9373149.
Yin X, Rozakis-Adcock M (2002). "Genomic organization and expression of the human tumorous imaginal disc (TID1) gene".Gene.278 (1–2):201–10.doi:10.1016/S0378-1119(01)00720-X.PMID11707338.
