| DNAJC28 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | DNAJC28 , C21orf55, C21orf78, DnaJ heat shock protein family (Hsp40) member C28 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | MGI: 2181053; HomoloGene: 9869; GeneCards: DNAJC28; OMA:DNAJC28 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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DnaJ homolog subfamily C member 28 is a protein that in humans is encoded by the DNAJC28 gene. [5] It's a member of chaperone DnaJ family. The family is also known as Hsp40 (heat shock protein 40 kDa).
The DNAJC28 gene is located on the negative strand of Chromosome 21 (21q22.11), spanning 3,784 base pairs. [9] Also known as C21orf78 or (previously) C21orf55 in humans, this gene has orthologs in animals, plants, and fungi. [10] DNAJC28 has only 2 exons, the first of which is the only one that differs between transcript variants.
DNAJC28 has a total of 3 transcriptional variants, all of which differ from transcript variant 1 in the 5’ UTR and encode an identical protein. All transcripts contain the same 2 exons, with exon 2 completely containing the coding sequence. [11]
| DNAJC28 Transcript Variant Number | Accession Number | mRNA length (nucleotides) | 5'UTR length (nucleotides) | Protein Length (amino acids) |
|---|---|---|---|---|
| 1 | NM_017833.5 | 1706 | 367 | 388 |
| 2 | NM_001040192.3 | 1485 | 146 | 388 |
| 3 | NM_001320746.3 | 1462 | 123 | 388 |
The protein DNAJC28 is 388 amino acids long and contains a conserved N-terminal J (DnaJ) domain, which is critical for interaction with Hsp70s. [12] Molecular weight and isoelectric point of human DNAJC28 without post-translational modification are 45.8 kDal and 9.57 pI, respectively. [13] [14] DNAJC28 has no isoforms. [5] No pattern was found across orthologs for amino acid composition. [13]
DNAJC28 contains a J domain, which is a defining feature of the DnaJ/Hsp40 family. J domains are highly conserved and are an integral part of protein translation, folding, translocation, and degradation through stimulating the ATPase activity of members of the Hsp70 family. [15] Each J domain is around 70 base pairs long, composed of four alpha helices, and have a highly conserved His-Pro-Asp (HPD) tripeptide motif between the second and third helices. [16] [17]
There is a conserved domain of unknown function (DUF1992) from amino acids 203-272. [18]
There is a coiled-coil region from approximately amino acids 288 to 318 that is conserved throughout all listed orthologs (through fungi and plants). [19] [20]
The E. coli DnaJ protein's J domain has been extensively analyzed and found to be of very similar tertiary structure to J domains of other members of the DnaJ family. [21] DNAJC28's J domain tertiary structure was predicted and annotated based off of the characteristics of other J domains.
DNAJC28 was found to mostly interact with proteins involved with the mitochondria and mitochondrial ATP synthase. Mitochondrial Hsp70 is also known to control F1F0 ATP synthase assembly and control the quality of F1F0 ATP synthase components. [22] [23] Other mitochondrial protein interactions were found on BioGrid. [24] [25]
| Hit | Full Name | Function | Location | Score |
|---|---|---|---|---|
| IARS2 | isoleucyl-tRNA synthetase 2, mitochondrial | Catalyze aminoacylation of tRNA by linking cognate amino acid | Mitochondria, cytoplasm | 935 |
| LETM1 | leucine zipper and EF-hand containing transmembrane protein 1 | Maintains mitochondrial tubular shapes, required for cellular viability | Inner mitochondrial membrane | 1535 |
| SLC30A9 | solute carrier family 30 member 9 | Enables zinc ion transmembrane transporter activity, regulates mitochondria organization | Mitochondrial membrane, ER, cytoplasm | 1570 |
| TIMM44 | translocase of inner mitochondrial membrane 44 | Mediates binding of Hsp70 to translocase of inner mitochondrial membrane 23 complex | Mitochondrial membrane | 2270 |
There are three distinct subfamilies within the DnaJ family, of which subfamily A has the most taxonomically distant homolog of E. coli DnaJ, suggesting that it evolved earlier in history than the other subfamilies. [26] DNAJC28 has its most distant orthologs in fungi. There are many DnaJ pseudogenes that are homologous only to part of the J-protein but tend to lack a majority of it. [27]
DNAJC28 has one distant paralog, Component of Oligomeric Golgi Complex 4 (COG4). [28] [29] COG4’s corresponding protein is a component of an oligomeric protein complex in the golgi apparatus that is involved in its structure and function, specifically retrograde transport. [30]
The gene DNAJC28 is evolving relatively slowly since it is not evolving much faster than Cytochrome C and is significantly slower than Fibrinogen Alpha, as shown by the dark blue trendline.
| Organism Type | Species Name | Common Name | Taxonomic Group | Date of Divergence | % Identity | % Similarity | Accession Number | Protein Length (Amino Acids) |
|---|---|---|---|---|---|---|---|---|
| Mammal | Homo sapiens | Human | Primates | 0 | 100.00% | 100.00% | NP_060303.2 | 388 |
| Mus musculus | House mouse | Rodentia | 87 | 72.49% | 79.70% | NP_001093208.1 | 409 | |
| Pteropus vampyrus | Large flying fox | Chiroptera | 94 | 86.49% | 93.30% | XP_011363977.1 | 384 | |
| Ornithorhynchus anatinus | Platypus | Monotremata | 180 | 68.32% | 79.40% | XP_007667935.2 | 381 | |
| Reptile | Alligator mississippiensis | American alligator | Crocodilia | 319 | 64.72% | 75.10% | XP_059576706.1 | 378 |
| Sphaerodactylus townsendi | Townsend's least gecko | Squamata | 319 | 60.50% | 73.10% | XP_048348340.1 | 374 | |
| Bird | Falco peregrinus | Peregrin falcon | Falconiformes | 319 | 59.47% | 73.30% | XP_055657544.1 | 372 |
| Gallus gallus | Chicken | Galliformes | 319 | 59.09% | 72.80% | XP_004934562.2 | 373 | |
| Amphibian | Bufo bufo | Common toad | Anura | 352 | 58.70% | 71.20% | XP_040279093.1 | 384 |
| Rhinatrema bivittatum | Two-lined caecilians | Gymnophiona | 352 | 58.01% | 71.90% | XP_029459412.1 | 379 | |
| Fish | Protopterus annectens | West African lungfish | Dipnoi | 408 | 50.82% | 67.40% | XP_043928883.1 | 374 |
| Latimeria chalumnae | West Indian Ocean coelacanth | Sarcopterygii | 415 | 54.80% | 74.50% | XP_006001534.1 | 379 | |
| Danio rerio | Zebrafish | Cyprinidae | 429 | 47.40% | 66.00% | NP_001017648.1 | 376 | |
| Callorhinchus milii | Australian ghostshark | Chondrichthyes | 462 | 54.23% | 64.30% | XP_007904164.1 | 376 | |
| Invertebrate | Drosophila melanogaster | Fruit fly | Insecta | 686 | 39.27% | 50.60% | AAY55603.1 | 355 |
| Fungi | Rhizopus microsporus | Fungal plant pathogen | Mucoraceae | 1275 | 46.67% | 26.80% | CEG77023.1 | 518 |
| Dacryopinax primogenitus | Jelly fungi | Basidiomycota | 1275 | 37.84% | 33.80% | XP_040633566.1 | 481 | |
| Rhizomucor pusillus | Human disease fungi | Lichtheimiaceae | 1275 | 35.00% | 34.50% | KAL1929861.1 | 329 | |
| Plant | Panicum virgatum | Switchgrass | Monocots | 1530 | 40.00% | 24.60% | XP_039855031.1 | 221 |
| Populus trichocarpa | Black cottonwood | Eudicots | 1530 | 37.14% | 26.20% | XP_002322905.3 | 221 | |
| Sphagnum troendelagicum | Norwegian peat moss | Bryophyta | 1530 | 36.50% | 34.50% | CAK9220607.1 | 261 |
A mitochondrial presequence was predicted from amino acids 7-39. Amino acids 7-16 are a highly positively charged amphiphilicity region. [31] A mitochondrial targeting signal presequence traditionally has a high composition of arginine, a very low amount of negatively charged residues at the N-terminus, and forms an amphipathic helix with a positively charged side and a hydrophobic side opposite it. [32] [33] All of which are features of the DNAJC28 targeting presequence. The mitochondrial presequence cleavage site is predicted to be at amino acid 48. [34]
There is low, ubiquitous expression of DNAJC28 in all human tissues. [35] DNAJC28 is also expressed in almost all parts of the mouse brain, excluding the hypothalamus and pons. [36]
The DnaJ/Hsp40 family is one of the largest groups of molecular chaperones, characterized by their possession of a J domain (or DnaJ domain), which interacts with Hsp70. [37] Hsp40s bind misfolded polypeptides or protein aggregates and deliver them to Hsp70 substrate-binding domains, greatly stimulating ATPase activity in the Hsp70 nucleotide-binding domain. [16] Heat Shock Protein genes are generally activated when the cell is exposed to stress, such as high temperature, infection, and low oxygen. [38] Subfamily C, which contains DNAJC28, is defined only by the presence of a J domain, not by the location of that J domain or specific-amino-acid rich sequences like the other two subfamilies. Members of subfamily C generally only interact with a limited number of substrates or do not bind directly to a substrate at all. Some Hsp40 proteins, instead of working with Hsp70, assist polypeptide movement through the mitochondrial translocon. [16]
The HPD tripeptide motif of the J domain interacts with key regions of Hsp70 proteins, specifically the Hsp70 linker and nucleotide-binding domain (NBD) crevice, which then restricts the Hsp70 protein in an optimal position for ATP hydrolysis. [21] The J domain also interacts with the Hsp70 substrate-binding domain β (SBDβ) to make signal transmission more efficient from the SBD to the NBD, greatly increasing affinity between the Hsp70 ADP-bound equilibrium state and substrates. [39]
The Hsp70/Hsp40 chaperone system works in proteostasis processes, which involves breaking down protein aggregations like a-synuclein which accumulates in Parkinson’s disease. [40] A study found that damaging missense variants of DNAJC28 are likely related to sporadic late-onset Parkinson’s disease. [41]
DNAJC28 was found to be excessively expressed in the hippocampus of the lupus-prone mice model MRL/lpr during TWEAK (TNF-like weak inducer of apoptosis) activation, which is associated with the neuropsychiatric impacts of lupus. That overexpression could either be damaging or a protective response to lupus. [42] Overexpression of other genes in the DnaJ family has been shown to contribute to neuroprotective effects in multiple neurodegenerative disease models. [43] Hsp70 are also know to be a crucial, suppressive part of the intrinsic apoptosis pathway. [44]
No DNAJC28 SNPs were found to have clinical significance. [45]
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. 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. 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. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.
In molecular biology, chaperone DnaJ, also known as Hsp40, is a molecular chaperone protein. It is expressed in a wide variety of organisms from bacteria to humans.
Transmembrane protein 241 is a ubiquitous sugar transporter protein which in humans is encoded by the TMEM241 gene.
C8orf48 is a protein that in humans is encoded by the C8orf48 gene. C8orf48 is a nuclear protein specifically predicted to be located in the nuclear lamina. C8orf48 has been found to interact with proteins that are involved in the regulation of various cellular responses like gene expression, protein secretion, cell proliferation, and inflammatory responses. This protein has been linked to breast cancer and papillary thyroid carcinoma.
Chromosome 10 open reading frame 67 (C10orf67), also known as C10orf115, LINC01552, and BA215C7.4, is an un-characterized human protein-coding gene. Several studies indicate a possible link between genetic polymorphisms of this and several other genes to chronic inflammatory barrier diseases such as Crohn's Disease and sarcoidosis.
Leukocyte Receptor Cluster Member 9 is an uncharacterized protein encoded by the LENG9 gene. In humans, LENG9 is predicted to play a role in fertility and reproductive disorders associated with female endometrium structures.
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Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
Chromosome 21 Open Reading Frame 58 (C21orf58) is a protein that in humans is encoded by the C21orf58 gene.
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Chromosome 19 open reading frame 44 is a protein that in humans is encoded by the C19orf44 gene. C19orf44 is an uncharacterized protein with an unknown function in humans. C19orf44 is non-limiting implying that the protein exists in other species besides human. The protein contains one domain of unknown function (DUF) that is highly conserved throughout its orthologs. This protein is most highly expressed in the testis and ovary, but also has significant expression in the thyroid and parathyroid. Other names for this protein include: LOC84167.
CAP-Gly Domain Containing Linker Protein Family Member 4 is a protein that in humans is encoded by the CLIP4 gene. In terms of conserved domains, the CLIP4 gene contains primarily ankyrin repeats and the eponymous CAP-Gly domains. The structure of the CLIP4 protein is largely made up of coil, with alpha helices dominating the rest of the protein. CLIP4 mRNA expression occurs largely in the adrenal cortex and atrioventricular node. The literature encompassing CLIP4's conserved domains and paralogs points toward microtubule regulation as a possible function of CLIP4.
Chromosome 9 open reading frame 85, commonly known as C9orf85, is a protein in Homo sapiens encoded by the C9orf85 gene. The gene is located at 9q21.13. When spliced, four different isoforms are formed. C9orf85 has a predicted molecular weight of 20.17 kdal. Isoelectric point was found to be 9.54. The function of the gene has not yet been confirmed, however it has been found to show high levels of expression in cells of high differentiation.
Chromosome 3 open reading frame 38 (C3orf38) is a protein which in humans is encoded by the C3orf38 gene.
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Chromosome 13 Open Reading Frame 46 is a protein which in humans is encoded by the C13orf46 gene. In humans, C13orf46 is ubiquitously expressed at low levels in tissues, including the lungs, stomach, prostate, spleen, and thymus. This gene encodes eight alternatively spliced mRNA transcript, which produce five different protein isoforms.
CFAP97D2 is a protein that in humans is encoded by the CFAP97D2 gene.
C6orf118 is a protein in humans, which is encoded by the C6orf118 gene. The protein domain, translin-associated factor X-interacting N-terminus (TRAX), is involved in RNA binding and RNA nuclease activity and in the regulation of mitochondrial function and cellular homeostasis. TRAX interacts with translin, a DNA-binding protein that binds to consensus sequences at breakpoint junctions of chromosomal translocation. TRAX in general contains bipartite nuclear targeting sequences, which may provide nuclear transport for translin, as translin lacks any nuclear targeting motifs. This protein is localized to the mitochondria.
Chromosome 10 open reading frame 95 is a protein that in humans is encoded by the c10orf95 gene. The protein is involved in pre-mRNA splicing and is localized to the nucleus in most tissues.
