DNAJC5
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
[uredi | uredi izvor]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
[uredi | uredi izvor]Dužina polipeptidnog lanca je 198 aminokiselina, a molekulska težina 22.149 kDa.[5]
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
[uredi | uredi izvor]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
[uredi | uredi izvor]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
[uredi | uredi izvor]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 Gα 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
[uredi | uredi izvor]Pokazalo se da DNAJC5 reaguje sa regulatorom transmembranske provodljivosti cistadte fibroze.[19]
Klinički značaj
[uredi | uredi izvor]Mutacije ovog gena mogu uzrokovati neuronsku ceroidnu lipofuscinozu.[20]
Reference
[uredi | uredi izvor]- ^ 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.
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- ^ 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.
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- ^ 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
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