Biology:DNAJC5

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

DnaJ homolog subfamily C member 5, also known as cysteine string protein or CSP is a protein, that in humans encoded by the DNAJC5 gene.[1] It was first described in 1990.[2]

Gene

In humans, the gene is located on the long arm of chromosome 20 (20q13.33) on the Watson (positive strand). The gene is 40,867 bases in length and the encoded protein has 198 amino acids with a predicted molecular weight of 22.149 kilodaltons (kDa). The weight of the mature protein is 34 kDa.

This gene is highly conserved and found both in invertebrates and vertebrates. In humans, a pseudogene of this gene is located on the short arm of chromosome 8.

Structure

The organisation of the protein is as follows:[3]

Tissue distribution

This protein is abundant in neural tissue and displays a characteristic localization to synaptic and clathrin coated vesicles. It is also found on secretory vesicles in endocrine, neuroendocrine and exocrine cells. This protein makes up ~1% of the protein content of the synaptic vesicles.[4] DNAJC5 appears to have a role in stimulated exocytosis.[5]

Function

The encoded protein is a member of the J protein family. These proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins (Hsp70). DNAJC5 is a guanine nucleotide exchange factor for Gα proteins.[6] CSPα plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. It is known to play a role in cystic fibrosis and Huntington's disease.[1]

This protein has been proposed as a key element of the synaptic molecular machinery devoted to the rescue of synaptic proteins that have been unfolded by activity dependent stress.[7][8] Syntaxin 1A, a plasma membrane SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) critical for neurotransmission, forms a complex with CSPα, a G protein and an N-type calcium channel. Huntingtin may be able displace both syntaxin 1A and CSPα from N-type channels.[9] CSP interacts with the calcium sensor protein synaptotagmin 9 via its linker domain.[10]

Huntingtin-interacting protein 14, a palmitoyl transferase, is required for exocytosis and targeting of CSP to synaptic vesicles. The palmitoyl residues are transferred to the cysteine residues. If these resides are mutated membrane targeting is reduced or lost.[11] The rat CSP forms a complex with Sgt (SGTA) and Hsc70 (HSPA8) located on the synaptic vesicle surface. This complex functions as an ATP-dependent chaperone that reactivates denatured substrates. Furthermore, the Csp/Sgt/Hsc70 complex appears to be important for maintenance of normal synapses.[3]

Its expression may be increased with the use of lithium.[12] Quercetin promotes formation of stable CSPα-CSPα dimers.[13]

Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis.[14]

Interactions

DNAJC5 has been shown to interact with the cystic fibrosis transmembrane conductance regulator.[15]

Clinical significance

Mutations in this gene may cause neuronal ceroid lipofuscinosis.[16]

References

  1. ↑ 1.0 1.1 "Entrez Gene: DNAJC5 DnaJ (Hsp40) homolog, subfamily C, member 5". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=80331. 
  2. ↑ "A cysteine-string protein is expressed in retina and brain of Drosophila". J. Neurogenet. 7 (1): 15–29. November 1990. doi:10.3109/01677069009084150. PMID 2129171. 
  3. ↑ 3.0 3.1 "A trimeric protein complex functions as a synaptic chaperone machine". Neuron 31 (6): 987–99. September 2001. doi:10.1016/S0896-6273(01)00427-5. PMID 11580898. 
  4. ↑ "Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis". PLOS ONE 6 (11): e26741. 2011. doi:10.1371/journal.pone.0026741. PMID 22073189. 
  5. ↑ "Cysteine string protein is required for calcium secretion coupling of evoked neurotransmission in drosophila but not for vesicle recycling". J. Neurosci. 18 (3): 956–64. February 1998. doi:10.1523/JNEUROSCI.18-03-00956.1998. PMID 9437017. 
  6. ↑ "The CSPalpha/G protein complex in PC12 cells". Biochem. Biophys. Res. Commun. 352 (1): 123–9. January 2007. doi:10.1016/j.bbrc.2006.10.178. PMID 17113038. 
  7. ↑ "The synaptic vesicle protein CSP alpha prevents presynaptic degeneration". Neuron 42 (2): 237–51. April 2004. doi:10.1016/S0896-6273(04)00190-4. PMID 15091340. 
  8. ↑ "Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration". Cell 123 (3): 383–96. November 2005. doi:10.1016/j.cell.2005.09.028. PMID 16269331. 
  9. ↑ "The cysteine string protein multimeric complex". Biochem. Biophys. Res. Commun. 348 (1): 83–91. September 2006. doi:10.1016/j.bbrc.2006.07.033. PMID 16875662. 
  10. ↑ "A charged prominence in the linker domain of the cysteine-string protein Cspα mediates its regulated interaction with the calcium sensor synaptotagmin 9 during exocytosis". FASEB J. 25 (1): 132–43. January 2011. doi:10.1096/fj.09-152033. PMID 20847230. 
  11. ↑ "The cysteine-string domain of the secretory vesicle cysteine-string protein is required for membrane targeting". Biochem. J. 335 (2): 205–9. October 1998. doi:10.1042/bj3350205. PMID 9761715. 
  12. ↑ "Lithium ions enhance cysteine string protein gene expression in vivo and in vitro". J. Neurochem. 74 (6): 2365–72. June 2000. doi:10.1046/j.1471-4159.2000.0742365.x. PMID 10820197. 
  13. ↑ "Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission". PLOS ONE 5 (6): e11045. 2010. doi:10.1371/journal.pone.0011045. PMID 20548785. 
  14. ↑ "Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis in Drosophila". J. Neurosci. 20 (16): 6039–47. August 2000. doi:10.1523/jneurosci.20-16-06039.2000. PMID 10934253. 
  15. ↑ "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58. August 2002. doi:10.1074/jbc.M111706200. PMID 12039948. 
  16. ↑ "Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis". American Journal of Human Genetics 89 (2): 241–52. August 2011. doi:10.1016/j.ajhg.2011.07.003. PMID 21820099. 

Further reading

External links



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