DNAJC5

DNAJC5
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2N05, 2N04
Identifikatori
Aliasi	DNAJC5
Vanjski ID-jevi	OMIM: 611203 MGI: 892995 HomoloGene: 9631 GeneCards: DNAJC5
Lokacija gena (čovjek)
Hrom.	Hromosom 20 (čovjek)
Kraj	63,936,031 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	181,196,926 bp
Ontologija gena
Molekularna funkcija	• ATP-dependent protein binding; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• Melanosom; • lysosomal membrane; • terminal bouton; • ćelijska membrana; • clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane; • Egzosom; • mitohondrija; • Sinapsna vezikula; • membrana; • azurophil granule membrane; • specific granule membrane; • Nervno-mišićna veza; • presynapse; • anchored component of synaptic vesicle membrane;
Biološki proces	• GO:1904089 negative regulation of neuron apoptotic process; • regulated exocytosis; • GO:0010554 neurotransmitter secretion; • synaptic vesicle exocytosis; • Egzocitoza; • neutrophil degranulation; • chaperone-mediated protein folding; • regulation of synaptic vesicle cycle;
	Izvori:Amigo / QuickGO
Ortolozi
	80331
	13002
	ENSG00000101152
	ENSMUSG00000000826
	Q9H3Z4
	P60904
	NM_025219
	NM_001271584; NM_001271585; NM_016775
	NP_079495
	NP_001258513; NP_001258514; NP_058055
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Homolog člana 5 DnaJ natporodice C, također poznat i kao cisteinski string protein ili CSP jest protein koji je kod ljudi kodiran genom DNAJC5 sa hromosoma 2o.^[5] Po prvi puta opisan je 1990.^[6]

Gen

Kod ljudi, gen se nalazi na dugom kraku hromosoma 20 (20q13.33) na Watsonovom (pozitivni+om) lancu. Dug 40.867 nukleobaza, a kodirani protein ima 198 aminokiselina sa predviđenom molekulskom težinom od 22.149 kiloDa (kDa). Težina zrelog proteina je 34 kDa.

Ovaj gen je visoko konzerviran i nalazi se i kod beskičmenjaka i kod kičmenjaka. Kod ljudi, pseudogen ovog gena nalazi se na kratkom kraku hromosoma 8.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 198 aminokiselina, a molekulska težina 22.149 kDa.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MADQRQRSLS	TSGESLYHVL	GLDKNATSDD	IKKSYRKLAL	KYHPDKNPDN
PEAADKFKEI	NNAHAILTDA	TKRNIYDKYG	SLGLYVAEQF	GEENVNTYFV
LSSWWAKALF	VFCGLLTCCY	CCCCLCCCFN	CCCGKCKPKA	PEGEETEFYV
SPEDLEAQLQ	SDEREATDTP	IVIQPASATE	TTQLTADSHP	SYHTDGFN

Struktura

Organizacija proteina je sljedeća:^[7]

N-terminal ima mjesto fosforilacije za protein-kinazu A
J domen (~70 aminokiselina)
regija linkera
cisteinski motiv koji se sastoji od 13–15 cisteina unutar niza od 25 aminokiselina. Jako je palmitoiliran u motivu cisteinske žice.
manje konzerviran C-terminalni domen

Tkivna distribucija

Ovaj protein je u izobilju u nervnom tkivu, karakterističnu lokaliziran na sinapsnim i klatrinom obloženim vezikulama. Također se nalazi na sekretornim vezikulama u endokrinim, neuroendokrinim i egzokrinim ćelijama. Ovaj protein čini ~1% sadržaja proteina sinapsnih vezikula.^[8] DNAJC5 ima ulogu u stimuliranju egzocitoza.^[9]

Funkcija

Kodirani protein je član porodice J proteina. Ovi proteini funkcionišu u mnogim ćelijskim procesima, tako što regulišu aktivnost ATPaza, 70 kDa-skih proteina toplotnog šoka (Hsp70). DNAJC5 je faktor zamjene guaninskih nukleotida za G_α proteine.^[10] CSPα ima ulogu u membranskom prometu i savijanju proteina, a pokazalo se da ima neurodegenerativna svojstva. Poznato je da ima ulogu u cistastoj fibrozi i Huntingtonovoj bolesti.^[5]

Ovaj protein je predložen kao ključni element sinapsnog molekulskog mehanizma za spašavanje sinapsnih proteina koji su se razvili stresom ovisnom o aktivnosti.^[11]^[12] Sintaksin 1A, membranski SNARE (topivi N-etilmaleimid-senzitivni faktor vezani protein receptor) kritičan za neurotransmisiju, formira kompleks sa CSPα, G- proteinom i N-tip kalcijskog kanala. Huntingtin možda može istisnuti i sintaksin 1A i CSPα iz kanala N-tipa.^[13] CSP stupa u interakciju sa proteinom senzora kalcija sinaptotagminom 9 preko svog linkerskog domena.^[14]

Protein 14 u interakciji s huntingtinom, palmitoil-transferaza, potreban je za egzocitozu i ciljanje CSP-a na sinapsnim vezikulama. Ostaci palmitoila prenose se na ostatke cisteina. Ako su ovi ostaci mutirani, ciljanje na membranu je smanjeno ili izgubljeno.^[15] Pacovski CSP formira kompleks sa Sgt (SGTA) i Hsc70 (HSPA8) koji se nalaze na površini sinapsne vezikule. Ovaj kompleks funkcionira kao ATP- ovisni šaperon koji reaktivira denaturirane supstrate. Nadalje, čini se da je kompleks Csp/Sgt/Hsc70 važan za održavanje normalne sinapse.^[7]

INjegova ekspresija se može povećati upotrebom litija.^[16] Kvercetin podstiče formiranje stabilnih dimera CSPα-CSPα.^[17]

Protein cisteinske žice povećava osjetljivost na kalcij kod egzocitoze neurotransmitera.^[18]

Interakcije

Pokazalo se da DNAJC5 reaguje sa regulatorom transmembranske provodljivosti cistadte fibroze.^[19]

Klinički značaj

Mutacije ovog gena mogu uzrokovati neuronsku ceroidnu lipofuscinozu.^[20]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000101152 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000000826 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c "Entrez Gene: DNAJC5 DnaJ (Hsp40) homolog, subfamily C, member 5".
^ Zinsmaier KE, Hofbauer A, Heimbeck G, Pflugfelder GO, Buchner S, Buchner E (novembar 1990). "A cysteine-string protein is expressed in retina and brain of Drosophila". J. Neurogenet. 7 (1): 15–29. doi:10.3109/01677069009084150. PMID 2129171.
^ ^a ^b Tobaben S, Thakur P, Fernández-Chacón R, Südhof TC, Rettig J, Stahl B (septembar 2001). "A trimeric protein complex functions as a synaptic chaperone machine". Neuron. 31 (6): 987–99. doi:10.1016/S0896-6273(01)00427-5. hdl:11858/00-001M-0000-0012-F746-0. PMID 11580898. S2CID 12386691.
^ Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C (2011). "Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis". PLOS ONE. 6 (11): e26741. doi:10.1371/journal.pone.0026741. PMC 3208569. PMID 22073189.
^ Ranjan R, Bronk P, Zinsmaier KE (februar 1998). "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. doi:10.1523/JNEUROSCI.18-03-00956.1998. PMC 6792780. PMID 9437017.
^ Bai L, Swayne LA, Braun JE (januar 2007). "The CSPalpha/G protein complex in PC12 cells". Biochem. Biophys. Res. Commun. 352 (1): 123–9. doi:10.1016/j.bbrc.2006.10.178. PMID 17113038.
^ Fernández-Chacón R, Wölfel M, Nishimune H, Tabares L, Schmitz F, Castellano-Muñoz M, Rosenmund C, Montesinos ML, Sanes JR, Schneggenburger R, Südhof TC (april 2004). "The synaptic vesicle protein CSP alpha prevents presynaptic degeneration". Neuron. 42 (2): 237–51. doi:10.1016/S0896-6273(04)00190-4. PMID 15091340. S2CID 15604376.
^ Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC (novembar 2005). "Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration". Cell. 123 (3): 383–96. doi:10.1016/j.cell.2005.09.028. PMID 16269331. S2CID 18173864.
^ Swayne LA, Beck KE, Braun JE (septembar 2006). "The cysteine string protein multimeric complex". Biochem. Biophys. Res. Commun. 348 (1): 83–91. doi:10.1016/j.bbrc.2006.07.033. PMID 16875662.
^ Boal F, Laguerre M, Milochau A, Lang J, Scotti PA (januar 2011). "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. doi:10.1096/fj.09-152033. PMID 20847230. S2CID 7494452.
^ Chamberlain LH, Burgoyne RD (oktobar 1998). "The cysteine-string domain of the secretory vesicle cysteine-string protein is required for membrane targeting". Biochem. J. 335 (2): 205–9. doi:10.1042/bj3350205. PMC 1219770. PMID 9761715.
^ Cordeiro ML, Umbach JA, Gundersen CB (juni 2000). "Lithium ions enhance cysteine string protein gene expression in vivo and in vitro". J. Neurochem. 74 (6): 2365–72. doi:10.1046/j.1471-4159.2000.0742365.x. PMID 10820197. S2CID 19687617.
^ Xu F, Proft J, Gibbs S, Winkfein B, Johnson JN, Syed N, Braun JE (2010). "Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission". PLOS ONE. 5 (6): e11045. doi:10.1371/journal.pone.0011045. PMC 2883571. PMID 20548785.
^ Dawson-Scully K, Bronk P, Atwood HL, Zinsmaier KE (august 2000). "Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis in Drosophila". J. Neurosci. 20 (16): 6039–47. doi:10.1523/jneurosci.20-16-06039.2000. PMC 6772598. PMID 10934253.
^ Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA (august 2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58. doi:10.1074/jbc.M111706200. PMID 12039948.
^ 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 (august 2011). "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. doi:10.1016/j.ajhg.2011.07.003. PMC 3155175. PMID 21820099.

Dopunska literatura

Chamberlain LH, Burgoyne RD (2000). "Cysteine string protein: the chaperone at the synapse". J. Neurochem. 74 (5): 1781–1789. doi:10.1046/j.1471-4159.2000.0741781.x. PMID 10800920. S2CID 7667658.
Mastrogiacomo A, Parsons SM, Zampighi GA, Jenden DJ, Umbach JA, Gundersen CB (1994). "Cysteine string proteins: a potential link between synaptic vesicles and presynaptic Ca2+ channels". Science. 263 (5149): 981–82. doi:10.1126/science.7906056. PMID 7906056.
Gundersen CB, Mastrogiacomo A, Faull K, Umbach JA (1994). "Extensive lipidation of a Torpedo cysteine string protein". Journal of Biological Chemistry. 269 (30): 19197–19199. doi:10.1016/S0021-9258(17)32151-8. PMID 8034679.
Mastrogiacomo A, Gundersen CB (1995). "The nucleotide and deduced amino acid sequence of a rat cysteine string protein". Molecular Brain Research. 28 (1): 12–18. doi:10.1016/0169-328x(94)00172-b. PMID 7535880.
Coppola T, Gundersen C (1996). "Widespread expression of human cysteine string proteins". FEBS Lett. 391 (3): 269–72. doi:10.1016/0014-5793(96)00750-8. PMID 8764987. S2CID 10410573.
Zhang H, Kelley WL, Chamberlain LH, et al. (1999). "Mutational analysis of cysteine-string protein function in insulin exocytosis". J. Cell Sci. 112 (9): 1345–51. doi:10.1242/jcs.112.9.1345. PMID 10194413.
Hattori A, Okumura K, Nagase T, et al. (2001). "Characterization of long cDNA clones from human adult spleen". DNA Res. 7 (6): 357–66. doi:10.1093/dnares/7.6.357. PMID 11214971.
Evans GJ, Wilkinson MC, Graham ME, et al. (2002). "Phosphorylation of cysteine string protein by protein kinase A. Implications for the modulation of exocytosis". J. Biol. Chem. 276 (51): 47877–85. doi:10.1074/jbc.M108186200. PMID 11604405.
Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature. 414 (6866): 865–71. doi:10.1038/414865a. PMID 11780052.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Miller LC, Swayne LA, Chen L, et al. (2004). "Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin". J. Biol. Chem. 278 (52): 53072–81. doi:10.1074/jbc.M306230200. PMID 14570907.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Giorgianni F, Beranova-Giorgianni S, Desiderio DM (2004). "Identification and characterization of phosphorylated proteins in the human pituitary". Proteomics. 4 (3): 587–98. doi:10.1002/pmic.200300584. PMID 14997482. S2CID 25355914.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
Boal F, Zhang H, Tessier C, et al. (2005). "The variable C-terminus of cysteine string proteins modulates exocytosis and protein-protein interactions". Biochemistry. 43 (51): 16212–23. doi:10.1021/bi048612+. PMID 15610015.
Natochin M, Campbell TN, Barren B, et al. (2005). "Characterization of the G alpha(s) regulator cysteine string protein". J. Biol. Chem. 280 (34): 30236–41. doi:10.1074/jbc.M500722200. PMID 15972823.
Zhang H, Schmidt BZ, Sun F, et al. (2006). "Cysteine string protein monitors late steps in cystic fibrosis transmembrane conductance regulator biogenesis". J. Biol. Chem. 281 (16): 11312–21. doi:10.1074/jbc.M512013200. PMID 16469739.
Chi A, Valencia JC, Hu ZZ, et al. (2007). "Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes". J. Proteome Res. 5 (11): 3135–44. doi:10.1021/pr060363j. PMID 17081065.

Vanjski linkovi

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101152 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000000826 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: DNAJC5 DnaJ (Hsp40) homolog, subfamily C, member 5".

[pmid2129171-6] Zinsmaier KE, Hofbauer A, Heimbeck G, Pflugfelder GO, Buchner S, Buchner E (novembar 1990). "A cysteine-string protein is expressed in retina and brain of Drosophila". J. Neurogenet. 7 (1): 15–29. doi:10.3109/01677069009084150. PMID 2129171.

[pmid11580898-7] Tobaben S, Thakur P, Fernández-Chacón R, Südhof TC, Rettig J, Stahl B (septembar 2001). "A trimeric protein complex functions as a synaptic chaperone machine". Neuron. 31 (6): 987–99. doi:10.1016/S0896-6273(01)00427-5. hdl:11858/00-001M-0000-0012-F746-0. PMID 11580898. S2CID 12386691.

[pmid22073189-8] Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C (2011). "Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis". PLOS ONE. 6 (11): e26741. doi:10.1371/journal.pone.0026741. PMC 3208569. PMID 22073189.

[pmid9437017-9] Ranjan R, Bronk P, Zinsmaier KE (februar 1998). "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. doi:10.1523/JNEUROSCI.18-03-00956.1998. PMC 6792780. PMID 9437017.

[pmid17113038-10] Bai L, Swayne LA, Braun JE (januar 2007). "The CSPalpha/G protein complex in PC12 cells". Biochem. Biophys. Res. Commun. 352 (1): 123–9. doi:10.1016/j.bbrc.2006.10.178. PMID 17113038.

[pmid15091340-11] Fernández-Chacón R, Wölfel M, Nishimune H, Tabares L, Schmitz F, Castellano-Muñoz M, Rosenmund C, Montesinos ML, Sanes JR, Schneggenburger R, Südhof TC (april 2004). "The synaptic vesicle protein CSP alpha prevents presynaptic degeneration". Neuron. 42 (2): 237–51. doi:10.1016/S0896-6273(04)00190-4. PMID 15091340. S2CID 15604376.

[pmid16269331-12] Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC (novembar 2005). "Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration". Cell. 123 (3): 383–96. doi:10.1016/j.cell.2005.09.028. PMID 16269331. S2CID 18173864.

[pmid16875662-13] Swayne LA, Beck KE, Braun JE (septembar 2006). "The cysteine string protein multimeric complex". Biochem. Biophys. Res. Commun. 348 (1): 83–91. doi:10.1016/j.bbrc.2006.07.033. PMID 16875662.

[pmid20847230-14] Boal F, Laguerre M, Milochau A, Lang J, Scotti PA (januar 2011). "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. doi:10.1096/fj.09-152033. PMID 20847230. S2CID 7494452.

[pmid9761715-15] Chamberlain LH, Burgoyne RD (oktobar 1998). "The cysteine-string domain of the secretory vesicle cysteine-string protein is required for membrane targeting". Biochem. J. 335 (2): 205–9. doi:10.1042/bj3350205. PMC 1219770. PMID 9761715.

[pmid10820197-16] Cordeiro ML, Umbach JA, Gundersen CB (juni 2000). "Lithium ions enhance cysteine string protein gene expression in vivo and in vitro". J. Neurochem. 74 (6): 2365–72. doi:10.1046/j.1471-4159.2000.0742365.x. PMID 10820197. S2CID 19687617.

[pmid20548785-17] Xu F, Proft J, Gibbs S, Winkfein B, Johnson JN, Syed N, Braun JE (2010). "Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission". PLOS ONE. 5 (6): e11045. doi:10.1371/journal.pone.0011045. PMC 2883571. PMID 20548785.

[pmid10934253-18] Dawson-Scully K, Bronk P, Atwood HL, Zinsmaier KE (august 2000). "Cysteine-string protein increases the calcium sensitivity of neurotransmitter exocytosis in Drosophila". J. Neurosci. 20 (16): 6039–47. doi:10.1523/jneurosci.20-16-06039.2000. PMC 6772598. PMID 10934253.

[pmid12039948-19] Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA (august 2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58. doi:10.1074/jbc.M111706200. PMID 12039948.

[pmid21820099-20] 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 (august 2011). "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. doi:10.1016/j.ajhg.2011.07.003. PMC 3155175. PMID 21820099.

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