DNAJC5 explained

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:

• 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

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.^[3] DNAJC5 appears to have a role in stimulated exocytosis.^[4]

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 G_α proteins.^[5] 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.^{[6] [7]} 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.^[8] CSP interacts with the calcium sensor protein synaptotagmin 9 via its linker domain.^[9]

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.^[10] 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.^[11]

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]

Further reading

• 10.1046/j.1471-4159.2000.0741781.x . Chamberlain LH, Burgoyne RD . Cysteine string protein: the chaperone at the synapse . J. Neurochem. . 74 . 5 . 1781–1789 . 2000 . 10800920 . 7667658 .
• Mastrogiacomo A, Parsons SM, Zampighi GA, Jenden DJ, Umbach JA, Gundersen CB . Cysteine string proteins: a potential link between synaptic vesicles and presynaptic Ca2+ channels . Science . 263 . 5149 . 981–82 . 1994 . 7906056 . 10.1126/science.7906056 .
• Gundersen CB, Mastrogiacomo A, Faull K, Umbach JA . Extensive lipidation of a Torpedo cysteine string protein . Journal of Biological Chemistry . 269 . 30 . 19197–19199 . 1994 . 10.1016/S0021-9258(17)32151-8 . 8034679 . free .
• Mastrogiacomo A, Gundersen CB . The nucleotide and deduced amino acid sequence of a rat cysteine string protein . Molecular Brain Research . 28 . 1 . 12–18 . 1995 . 7535880 . 10.1016/0169-328x(94)00172-b.
• Coppola T, Gundersen C . Widespread expression of human cysteine string proteins . FEBS Lett. . 391 . 3 . 269–72 . 1996 . 8764987 . 10.1016/0014-5793(96)00750-8 . 10410573 . free .
• Zhang H, Kelley WL, Chamberlain LH . Mutational analysis of cysteine-string protein function in insulin exocytosis . J. Cell Sci. . 112 . 9. 1345–51 . 1999 . 10.1242/jcs.112.9.1345 . 10194413 . etal.
• Hattori A, Okumura K, Nagase T . Characterization of long cDNA clones from human adult spleen . DNA Res. . 7 . 6 . 357–66 . 2001 . 11214971 . 10.1093/dnares/7.6.357 . etal. free .
• Evans GJ, Wilkinson MC, Graham ME . Phosphorylation of cysteine string protein by protein kinase A. Implications for the modulation of exocytosis . J. Biol. Chem. . 276 . 51 . 47877–85 . 2002 . 11604405 . 10.1074/jbc.M108186200 . etal. free .
• Deloukas P, Matthews LH, Ashurst J . The DNA sequence and comparative analysis of human chromosome 20 . Nature . 414 . 6866 . 865–71 . 2002 . 11780052 . 10.1038/414865a . 2001Natur.414..865D . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . etal . 2002PNAS...9916899M. free .
• Miller LC, Swayne LA, Chen L . Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin . J. Biol. Chem. . 278 . 52 . 53072–81 . 2004 . 14570907 . 10.1074/jbc.M306230200 . etal. free.
• Ota T, Suzuki Y, Nishikawa T . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . etal. free .
• Giorgianni F, Beranova-Giorgianni S, Desiderio DM . Identification and characterization of phosphorylated proteins in the human pituitary . Proteomics . 4 . 3 . 587–98 . 2004 . 14997482 . 10.1002/pmic.200300584 . 25355914 .
• Gerhard DS, Wagner L, Feingold EA . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Boal F, Zhang H, Tessier C . The variable C-terminus of cysteine string proteins modulates exocytosis and protein-protein interactions . Biochemistry . 43 . 51 . 16212–23 . 2005 . 15610015 . 10.1021/bi048612+. etal.
• Natochin M, Campbell TN, Barren B . Characterization of the G alpha(s) regulator cysteine string protein . J. Biol. Chem. . 280 . 34 . 30236–41 . 2005 . 15972823 . 10.1074/jbc.M500722200 . etal. free .
• Zhang H, Schmidt BZ, Sun F . Cysteine string protein monitors late steps in cystic fibrosis transmembrane conductance regulator biogenesis . J. Biol. Chem. . 281 . 16 . 11312–21 . 2006 . 16469739 . 10.1074/jbc.M512013200 . etal. free .
• Chi A, Valencia JC, Hu ZZ . Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes . J. Proteome Res. . 5 . 11 . 3135–44 . 2007 . 17081065 . 10.1021/pr060363j . etal.

External links

• GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinosis

Notes and References

1. Web site: Entrez Gene: DNAJC5 DnaJ (Hsp40) homolog, subfamily C, member 5.
2. Zinsmaier KE, Hofbauer A, Heimbeck G, Pflugfelder GO, Buchner S, Buchner E . A cysteine-string protein is expressed in retina and brain of Drosophila . J. Neurogenet. . 7 . 1 . 15–29 . November 1990 . 2129171 . 10.3109/01677069009084150.
3. Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C . Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis . PLOS ONE . 6 . 11 . e26741 . 2011 . 22073189 . 10.1371/journal.pone.0026741 . 3208569. free . 2011PLoSO...626741B .
4. Ranjan R, Bronk P, Zinsmaier KE . 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 . 9437017 . 10.1523/JNEUROSCI.18-03-00956.1998 . 6792780 .
5. Bai L, Swayne LA, Braun JE . The CSPalpha/G protein complex in PC12 cells . Biochem. Biophys. Res. Commun. . 352 . 1 . 123–9 . January 2007 . 17113038 . 10.1016/j.bbrc.2006.10.178 .
6. Fernández-Chacón R, Wölfel M, Nishimune H, Tabares L, Schmitz F, Castellano-Muñoz M, Rosenmund C, Montesinos ML, Sanes JR, Schneggenburger R, Südhof TC . The synaptic vesicle protein CSP alpha prevents presynaptic degeneration . Neuron . 42 . 2 . 237–51 . April 2004 . 15091340 . 10.1016/S0896-6273(04)00190-4. 15604376 . free .
7. Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC . Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration . Cell . 123 . 3 . 383–96 . November 2005 . 16269331 . 10.1016/j.cell.2005.09.028 . 18173864 . free .
8. Swayne LA, Beck KE, Braun JE . The cysteine string protein multimeric complex . Biochem. Biophys. Res. Commun. . 348 . 1 . 83–91 . September 2006 . 16875662 . 10.1016/j.bbrc.2006.07.033 .
9. Boal F, Laguerre M, Milochau A, Lang J, Scotti PA . 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 . 20847230 . 10.1096/fj.09-152033 . free . 7494452 .
10. Chamberlain LH, Burgoyne RD . The cysteine-string domain of the secretory vesicle cysteine-string protein is required for membrane targeting . Biochem. J. . 335 . 2. 205–9 . October 1998 . 9761715 . 1219770 . 10.1042/bj3350205.
11. Tobaben S, Thakur P, Fernández-Chacón R, Südhof TC, Rettig J, Stahl B . A trimeric protein complex functions as a synaptic chaperone machine . Neuron . 31 . 6 . 987–99 . September 2001 . 11580898 . 10.1016/S0896-6273(01)00427-5 . 11858/00-001M-0000-0012-F746-0 . 12386691 . free .
12. Cordeiro ML, Umbach JA, Gundersen CB . Lithium ions enhance cysteine string protein gene expression in vivo and in vitro . J. Neurochem. . 74 . 6 . 2365–72 . June 2000 . 10820197 . 10.1046/j.1471-4159.2000.0742365.x . 19687617 .
13. Xu F, Proft J, Gibbs S, Winkfein B, Johnson JN, Syed N, Braun JE . Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission . PLOS ONE . 5 . 6 . e11045 . 2010 . 20548785 . 2883571 . 10.1371/journal.pone.0011045 . free . 2010PLoSO...511045X .
14. Dawson-Scully K, Bronk P, Atwood HL, Zinsmaier KE. Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis in Drosophila . J. Neurosci. . 20 . 16 . 6039–47 . August 2000 . 10934253 . 10.1523/jneurosci.20-16-06039.2000. 6772598 . free .
15. Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA . 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 . 12039948 . 10.1074/jbc.M111706200 . free .
16. 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 . 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 . 21820099 . 10.1016/j.ajhg.2011.07.003 . 3155175.