DNAJC28

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]

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 kDa and 9.57 pI, respectively.^[13][14] DNAJC28 has no isoforms.^[5] No pattern was found across orthologs for amino acid composition.^[13]

Tertiary Structure

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.

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.

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 known to be a crucial, suppressive part of the intrinsic apoptosis pathway.^[44]

No DNAJC28 SNPs were found to have clinical significance.^[45]