DnaJ homolog subfamily C member 28 is a protein that in humans is encoded by the DNAJC28gene.[5] It's a member of chaperone DnaJ family. The family is also known as Hsp40 (heat shock protein 40 kDa).
DNAJC28 human gene location with surrounding genes. IFNGR2 encodes the beta chain of the gamma interferon receptor, and defects in it cause extreme immunodeficiency. TMEM50B is hypothesized to be involved in endosome to vacuole transportation. Neighboring GART is involved in de novo purine synthesis. SON encodes a protein that binds RNA, promotes pre-mRNA splicing, and recognizes a human Hepatitis B virus DNA sequence, repressing its core promoter activity.
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 transcriptional variants, numerically labeled on the left. The 2 exons are also labeled. Light green regions are untranslated while the dark green regions are the coding sequence.
RNA and Protein Products of Each DNAJC28 Transcript Variant
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]
Tertiary Structure
Predicted DNAJC28 J domain annotated with helices and HPD motif. Helix locations and shape were predicted using E. coli DnaJ protein. HPD motif is highlighted.
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 on the characteristics of other J domains.
Interacting Proteins
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]
Mediates binding of Hsp70 to translocase of inner mitochondrial membrane 23 complex
Mitochondrial membrane
2270
Orthologs
DNAJC28 Evolutionary History comparing median Date of Divergence from Homo sapiens (millions of years) and Corrected Sequence Divergence for DNAJC28, Cytochrome C, Fibrinogen Alpha, and COG4. Corrected sequence divergence was calculated using the percent identity between the protein sequences of the different species to humans.
There are three distinct subfamilies within the DnaJ family, of which subfamily A has the most taxonomically distant homolog of E. coliDnaJ, 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]
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.
DNAJC28 iTasser Model 2. N-terminus is colored red. The predicted mitochondrial presequence is pictured in green (amino acids 7-39), light green is the NCBI listed DnaJ domain, yellow is Helix 1 (52-56), teal is Helix 2 (64-78), orange is the HPD motif, blue is Helix 3 (85-99), purple is Helix 4 (105-112).
A mitochondrialpresequence 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]
Function
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]
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 known to be a crucial, suppressive part of the intrinsic apoptosis pathway.[44]
No DNAJC28 SNPs were found to have clinical significance.[45]
Gardiner K, Slavov D, Bechtel L, Davisson M (2002). "Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis". Genomics. 79 (6): 833–43. doi:10.1006/geno.2002.6782. PMID12036298.
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