DNAJC5

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.

The organisation of the protein is as follows:

• an N-terminus phosphorylation site for protein kinase A
• a J domain (~70 amino acids)
• a linker region
• a cysteine motif consisting of 13–15 cysteines within a stretch of 25 amino acids. It is heavily palmitoylated in the cysteine string motif.
• a less conserved C-terminal domain

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.{{cite journal | vauthors = Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C | title = Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e26741 | year = 2011 | pmid = 22073189 | doi = 10.1371/journal.pone.0026741 | pmc=3208569| doi-access = free | bibcode = 2011PLoSO...626741B }} DNAJC5 appears to have a role in stimulated exocytosis.{{cite journal | vauthors = Ranjan R, Bronk P, Zinsmaier KE | title = Cysteine string protein is required for calcium secretion coupling of evoked neurotransmission in drosophila but not for vesicle recycling | journal = J. Neurosci. | volume = 18 | issue = 3 | pages = 956–64 |date=February 1998 | pmid = 9437017 | doi = 10.1523/JNEUROSCI.18-03-00956.1998 | pmc = 6792780 }}

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 G_α proteins.{{cite journal | vauthors = Bai L, Swayne LA, Braun JE | title = The CSPalpha/G protein complex in PC12 cells | journal = Biochem. Biophys. Res. Commun. | volume = 352 | issue = 1 | pages = 123–9 |date=January 2007 | pmid = 17113038 | doi = 10.1016/j.bbrc.2006.10.178 }} 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.

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.{{cite journal | vauthors = Fernández-Chacón R, Wölfel M, Nishimune H, Tabares L, Schmitz F, Castellano-Muñoz M, Rosenmund C, Montesinos ML, Sanes JR, Schneggenburger R, Südhof TC | title = The synaptic vesicle protein CSP alpha prevents presynaptic degeneration | journal = Neuron | volume = 42 | issue = 2 | pages = 237–51 |date=April 2004 | pmid = 15091340 | doi = 10.1016/S0896-6273(04)00190-4| s2cid = 15604376 | doi-access = free }}{{cite journal | vauthors = Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC | title = Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration | journal = Cell | volume = 123 | issue = 3 | pages = 383–96 |date=November 2005 | pmid = 16269331 | doi = 10.1016/j.cell.2005.09.028 | s2cid = 18173864 | doi-access = free }} 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.{{cite journal | vauthors = Swayne LA, Beck KE, Braun JE | title = The cysteine string protein multimeric complex | journal = Biochem. Biophys. Res. Commun. | volume = 348 | issue = 1 | pages = 83–91 |date=September 2006 | pmid = 16875662 | doi = 10.1016/j.bbrc.2006.07.033 }} CSP interacts with the calcium sensor protein synaptotagmin 9 via its linker domain.{{cite journal | vauthors = Boal F, Laguerre M, Milochau A, Lang J, Scotti PA | title = 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 | journal = FASEB J. | volume = 25 | issue = 1 | pages = 132–43 |date=January 2011 | pmid = 20847230 | doi = 10.1096/fj.09-152033 | doi-access = free | s2cid = 7494452 }}

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.{{cite journal | vauthors = Chamberlain LH, Burgoyne RD | title = The cysteine-string domain of the secretory vesicle cysteine-string protein is required for membrane targeting | journal = Biochem. J. | volume = 335 | issue = 2| pages = 205–9 |date=October 1998 | pmid = 9761715 | pmc = 1219770 | doi = 10.1042/bj3350205}} 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.{{cite journal | vauthors = Tobaben S, Thakur P, Fernández-Chacón R, Südhof TC, Rettig J, Stahl B | title = A trimeric protein complex functions as a synaptic chaperone machine | journal = Neuron | volume = 31 | issue = 6 | pages = 987–99 |date=September 2001 | pmid = 11580898 | doi = 10.1016/S0896-6273(01)00427-5 | hdl = 11858/00-001M-0000-0012-F746-0 | s2cid = 12386691 | hdl-access = free }}

Its expression may be increased with the use of lithium.{{cite journal | vauthors = Cordeiro ML, Umbach JA, Gundersen CB | title = Lithium ions enhance cysteine string protein gene expression in vivo and in vitro | journal = J. Neurochem. | volume = 74 | issue = 6 | pages = 2365–72 |date=June 2000 | pmid = 10820197 | doi = 10.1046/j.1471-4159.2000.0742365.x | s2cid = 19687617 }} Quercetin promotes formation of stable CSPα-CSPα dimers.{{cite journal | vauthors = Xu F, Proft J, Gibbs S, Winkfein B, Johnson JN, Syed N, Braun JE | title = Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission | journal = PLOS ONE | volume = 5 | issue = 6 | pages = e11045 | year = 2010 | pmid = 20548785 | pmc = 2883571 | doi = 10.1371/journal.pone.0011045 | doi-access = free | bibcode = 2010PLoSO...511045X }}

Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis.{{cite journal | vauthors = Dawson-Scully K, Bronk P, Atwood HL, Zinsmaier KE| title = Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis in Drosophila | journal = J. Neurosci. | volume = 20 | issue = 16 | pages = 6039–47 |date=August 2000 | pmid = 10934253 | doi = 10.1523/jneurosci.20-16-06039.2000| pmc = 6772598 | doi-access = free }}

DNAJC5 has been shown to interact with the cystic fibrosis transmembrane conductance regulator.{{cite journal | vauthors = Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA | title = Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator | journal = J. Biol. Chem. | volume = 277 | issue = 32 | pages = 28948–58 |date=August 2002 | pmid = 12039948 | doi = 10.1074/jbc.M111706200 | doi-access = free }}

Mutations in this gene may cause neuronal ceroid lipofuscinosis.{{cite journal | vauthors = Nosková L, Stránecký V, Hartmannová H, Přistoupilová A, Barešová V, Ivánek R, Hůlková H, Jahnová H, van der Zee J, Staropoli JF, Sims KB, Tyynelä J, Van Broeckhoven C, Nijssen PC, Mole SE, Elleder M, Kmoch S | title = Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis | journal = American Journal of Human Genetics | volume = 89 | issue = 2 | pages = 241–52 |date=August 2011 | pmid = 21820099 | doi = 10.1016/j.ajhg.2011.07.003 | pmc=3155175}}

{{reflist|2}}

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{{refend}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1428/ GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinosis]

{{PDB Gallery|geneid=80331}}

{{Chaperones}}

Category:Heat shock proteins

Category:Co-chaperones