Transmembranski regulator provodljivosti cistaste fibroze

CFTR
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1XMI, 1XMJ, 2BBO, 2BBS, 2BBT, 2LOB, 2PZE, 2PZF, 2PZG, 3GD7, 3ISW, 4WZ6, 5D2D, 5D3E, 5D3F
Identifikatori
Aliasi	CFTR
Vanjski ID-jevi	OMIM: 602421 MGI: 88388 HomoloGene: 55465 GeneCards: CFTR
EC broj	5.6.1.6
Lokacija gena (čovjek)
Hrom.	Hromosom 7 (čovjek)
Kraj	117,715,971 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	18,322,767 bp
Ontologija gena
Molekularna funkcija	• nucleotide binding; • PDZ domain binding; • chloride transmembrane transporter activity; • GO:0001948, GO:0016582 vezivanje za proteine; • chloride channel inhibitor activity; • vezivanje enzima; • hydrolase activity; • ATP binding; • chloride channel activity; • ATPase-coupled inorganic anion transmembrane transporter activity; • chloride channel regulator activity; • ATPase-coupled transmembrane transporter activity; • intracellularly ATP-gated chloride channel activity; • ATPase activity; • bicarbonate transmembrane transporter activity; • chaperone binding; • Sec61 translocon complex binding; • isomerase activity;
Ćelijska komponenta	• citoplazma; • reciklirajući endosom; • endozom; • early endosome membrane; • membrana; • ćelijska membrana; • chloride channel complex; • cell surface; • lysosomal membrane; • early endosome; • Golgi-associated vesicle membrane; • endoplasmic reticulum Sec complex; • Egzosom; • citosol; • endosome membrane; • clathrin-coated vesicle membrane; • integral component of membrane; • apical plasma membrane; • Endoplazmatski retikulum; • endoplasmic reticulum membrane; • recycling endosome membrane; • integral component of plasma membrane; • jedro; • GO:0009327 makromolekulani kompleks;
Biološki proces	• positive regulation of cyclic nucleotide-gated ion channel activity; • intracellular pH elevation; • membrane hyperpolarization; • positive regulation of voltage-gated chloride channel activity; • cholesterol transport; • ion transport; • vesicle docking involved in exocytosis; • transmembrane transport; • sperm capacitation; • positive regulation of insulin secretion involved in cellular response to glucose stimulus; • cholesterol biosynthetic process; • positive regulation of exocytosis; • chloride transport; • cellular response to cAMP; • protein deubiquitination; • membrane organization; • chloride transmembrane transport; • transepithelial water transport; • multicellular organismal water homeostasis; • cellular response to forskolin; • bicarbonate transport; • GO:0015915 transport; • response to endoplasmic reticulum stress;
	Izvori:Amigo / QuickGO
Ortolozi
	1080
	12638
	ENSG00000001626
	ENSMUSG00000041301
	P13569
	P26361
	NM_000492
	NM_021050
	NP_000483
	NP_066388
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Transmembranski regulator provodljivosti cistaste fibroze (CFTR) je membranski protein i anionski kanal kod kičmenjaka, koji je kodiran genom CFTR sa hromosoma 7^[5]^[6]

Genetičar Lap-Chee Tsui i njegov tim identifikovali su CFTR gen 1989. |godine, kao gen povezan sa CF (cistaste fibroze).^[7]

Gen CFTR kodira ABC transportersku-klasu proteina ionski kanalionskog kanala koji provodi hlorid^[8] i bikarbonatne zone kroz epitelne ćelijske membrane. Mutacije gena CFTR koje utiču na funkciju anionskih kanala dovode do disregulacije transporta tečnosti epitelne obloge (sluzi) u plućima, pankreasu i drugim organima, što dovodi do cistaste fibroze. Komplikacije uključuju zgušnjavanje sluzi u plućima s čestim respiratornim infekcijama i insuficijencijama gušterače što dovodi do pothranjenosti i dijabetesa. Ova stanja dovode do hronične invalidnosti i smanjenog životnog vijeka. Kod muških pacijenata, progresivna opstrukcija i destrukcija razvojnog vas deferens (spermne vrpce) i epididimisa je rezultat abnormalnih intralumenskih sekrecija,^[9] uzrokujući urođeno odsustvo sjemenovoda i mušku neplodnost.

Gen

Gen koji kodira ljudski CFTR protein nalazi se na hromosomu 7, na poziciji q31.2 dugog kraka (q).^[6] od baznog para 116,907,253 do baznog para 117,095,955. CFTR ortolozi^[10] javljaju se kod viličastih kičmenjaka.^[11]

Svaki pojedinac nasljeđuje dvije kopije gena CFTR (regulator transmembranske provodljivosti cistaste fibroze). Međutim, neke od naslijeđenih kopija su izmijenjene. Do sada je CFTR gen povezan sa preko 700 različitih mutacija. Osoba sa CF nasljeđuje dvije defektne kopije CFTR gena. Ove mutacije mogu biti heterozigotne, što znači da uključuju dvije različite mutacije, i homozigotne, što znači da uključuju istu mutaciju. Delta F508 je najčešća mutacija, koja čini više od 70% svih mutacija. Oni koji su homozigoti za Delta F508 obično su pogođeni insuficijencijom pankreasa.^[12]

„CFTR“ gen je korišten kod životinja kao filogenetski marker jedarne DNK.^[10] Velike genomske sekvence ovog gena korištene su za istraživanje filogenije glavne grupe sisara,^[13] i potvrdio grupisanje placentalnih redova u četiri glavne klade: Xenarthra, Afrotheria, Laurasiatheria i Euarchonta plus Glires.

Mutacije

Opisano je skoro 1000 mutacija uzroka cistaste fibroze.^[14] Najčešća mutacija, DeltaF508 (ΔF508) prvenstveno poznata kao procesna mutacija koja je rezultat delecija (Δ) tri nukleotida, što rezultira gubitkom aminokiseline fenilalanina (F) na 508. poziciji na proteinu.^[15] Kao rezultat toga, protein se ne savija normalno i brže se razgrađuje. Velika većina mutacija je rijetka. Distribucija i učestalost mutacija varira među različitim populacijama što ima implikacije na genetički skrining i savjetovanje.

Otkrivanje lijekova za terapiju CF kod svih pacijenata je komplikovano zbog velikog broja mutacija koje uzrokuju bolest. U idealnom slučaju, potrebna je biblioteka ćelijskih linija i testova. baziranih na ćelijama koji odgovaraju svim mutantima za skrining široko aktivnih kandidata za lijekove. Metodi ćelijskog inženjerstva uključujući fluorogene oligonukleotidne signalne sonde mogu se koristiti za otkrivanje i izolaciju klonskih ćelijskih linija za svaki mutant.^[16]

Mutacije se sastoje od zamjene, dupliciranja, delecija ili skraćivanja gena CFTR. Ovo može dovesti do toga da proteini možda ne funkcionišu, rade manje efikasno, brže se razgrađuju ili su prisutni u nedovoljnom broju.^[17]

Pretpostavlja se da mutacije u CFTR genu mogu dati selektivnu prednost heterozigotnim osobama. Ćelije koje eksprimiraju mutantni oblik CFTR proteina otporne su na invaziju bakterije Salmonella typhi, uzročnika tifusne groznice, a miševi koji nose jednu kopiju mutantnog CFTR-a otporni su na dijareju uzrokovanu toksinom kolere.^[18]

Najčešće mutacije koje uzrokuju cistastu fibrozu i insuficijenciju pankreasa kod ljudi su:^[19]

Varijanta cDNK imena (naređeno od 5' do 3')	Naziv varijante proteina	Naslijeđeni naziv varijante	rsID	No alela u CFTR2	Alelna frekvencija u CFTR2	% Pankreasne nedovoljnosti	Konačno određivanje varijante (juli 2020.)
Naziv varijante proteina	Naslijeđeni naziv varijante	rsID	No alela u CFTR2	Alelna frekvencija u CFTR2	% Pankreasne nedovoljnosti	Konačno određivanje varijante (juli 2020.)	Varijanta naziva cDNK (naređeno od 5' do 3')	Naziv varijante proteina	Naslijeđeni naziv varijante	rsID	No alela u CFTR2	Alelna frekvencija u CFTR2	% Dovoljnosti pankreasa	Konačno određivanje varijante (juli 2020.)
c.1521_1523delCTT	p.Phe508del	F508del	rs113993960	99061	0,69744	98%	Uzrokuje CF
c.1624G>T	p.Gly542X	G542X	rs113993959	3610	0,02542	98%	Uzrokuje CF
c.1652G>A	p.Gly551Asp	G551D	rs75527207	2986	0,02102	96%	Uzrokuje CF
c.3909C>G	p.Asn1303Lys	N1303K	rs80034486	2246	0,01581	98%	Uzrokuje CF
c.350G>A	p.Arg117His	R117H	rs78655421	1854	0.01305	23%	Različite kliničke posljedice
c.3846G>A	p.Trp1282X	W1282X	rs77010898	1726	0,01215	99%	Uzrokuje CF
c.489+1G>T	Bez naziva proteina	621+1G->T	rs78756941	1323	0,00931	99%	uzrokuje CF
c.1657C>T	p.Arg553X	R553X	rs74597325	1323	0,00931	97%	Uzrokuje CF
c.1585-1G>A	Bez naziva proteina	1717-1G->A	rs76713772	1216	0,00856	97%	Uzrokuje CF
c.3718-2477C>T	Bez naziva proteina	3849+10kbC->T	rs75039782	1158	0,00815	33%	uzrokuje CF
c.2657+5G>A	Bez naziva proteina	2789+5G->A	rs80224560	1027	0,00723	43%	Izaziva CF
c.1519_1521delATC	p. Ile507del	I507del	rs121908745	651	0,00458	98%	Uzrokuje CF
c.3484C>T	p.Arg1162X	R1162X	rs74767530	651	0,00458	97%	Uzrokuje CF
c.254G>A	p.Gly85Glu	G85E	rs75961395	616	0.00434	85%	Uzrokuje CF
c.3454G>C	p.Asp1152His	D1152H	rs75541969	571	0,00402	24%	Varijabilne kliničke posljedice
c.2051_2052delAAinsG	p. Lys684SerfsX38	2183AA->G	rs121908799	542	0,00382	96%	Uzrokuje CF
c.3528delC	p. Lys1177SerfsX15	3659delC	rs121908747	539	0,00379	99%	Uzrokuje CF
c.1040G>C	p.Arg347Pro	R347P	rs77932196	533	0,00375	68%	Uzrokuje CF
c.1210−12T[5]	Bez naziva proteina	5T	rs1805177	516	0,00363	28%	Varijabilne kliničke posljedice
c.2988+1G>A	Bez naziva proteina	3120+1G->A	rs75096551	501	0,00353	98%	Uzrokuje CF
c.1364C>A	p.Ala455Glu	A455E	rs74551128	500	0,00352	34%	Uzrokuje CF
c.3140-26A>G	Bez naziva proteina	3272-26A->G	rs76151804	470	0,00331	29%	Uzrokuje CF
c.1000C>T	p.Arg334Trp	R334W	rs121909011	429	0,00302	40%	Uzrokuje CF
c.1766+1G>A	Bez naziva proteina	1898+1G->A	rs121908748	421	0,00296	99%	Izaziva CF
c.54-5940_273+10250del21kb	p.Ser18ArgfsX16	CFTRdele2,3	Nije pronađeno	417	0,00294	100%	Uzrokuje CF
c.1679G>C	p.Arg560Thr	R560T	rs80055610	343	0,00241	98%	Uzrokuje CF
c.617T>G	p. Leu206Trp	L206W	rs121908752	333	0,00234	20%	Uzrokuje CF
c.2052dupA	p.Gln685ThrfsX4	2184insA	rs121908786	329	0,00232	85%	Uzrokuje CF
c.262_263delTT	p. Leu88IlefsX22	394delTT	rs121908769	307	0,00216	97%	Uzrokuje CF
c.178G>T	p.Glu60X	E60X	rs77284892	296	0.00208	99%	Uzrokuje CF
c.1477C>T	p.Gln493X	Q493X	rs77101217	292	0,00206	98%	Uzrokuje CF
c.579+1G>T	Bez naziva proteina	711+1G->T	rs77188391	274	0,00193	98%	uzrokuje CF
c.2052delA	p. Lys684AsnfsX38	2184delA	rs121908746	255	0,00180	98%	Uzrokuje CF
c.200C>T	p.Pro67Leu	P67L	rs368505753	239	0,00168	34%	Uzrokuje CF
c.3302T>A	p.Met1101Lys	M1101K	rs36210737	238	0,00168	69%	Uzrokuje CF
c.1408A>G	p.Met470Val	M470V	rs213950	235	0,00165	46%	Ne izaziva CF
c.3276C>A ili c.3276C>G	p.Tyr1092X	Y1092X	rs121908761	225	0,00158	98%	Uzrokuje CF
c.3196C>T	p.Arg1066Cys	R1066C	rs78194216	220	0,00155	98%	Uzrokuje CF
c.1021_1022dupTC	p.Phe342HisfsX28	1154insTC	rs387906360	214	0,00151	99%	Uzrokuje CF
c.3773dupT	p. Leu1258PhefsX7	3905insT	rs121908789	210	0,00148	97%	Uzrokuje CF
c.1646G>A	p.Ser549Asn	S549N	rs121908755	203	0,00143	84%	Uzrokuje CF
c.1040G>A	p.Arg347His	R347H	rs77932196	199	0,00140	24%	Uzrokuje CF
c.948delT	p.Phe316LeufsX12	1078delT	rs121908744	184	0,00130	99%	Uzrokuje CF
c.1210-33_1210-6GT[12]T[4]	Bez naziva proteina	5T;TG12	Nije pronađeno	182	0,00128	14%	Varijabilne kliničke posljedice
c.3472C>T	p.Arg1158X	R1158X	rs79850223	179	0,00126	99%	Uzrokuje CF
c.2834C>T	p.Ser945Leu	S945L	rs397508442	167	0,00118	40%	Uzrokuje CF
c.1558G>T	p. Val520Phe	V520F	rs77646904	156	0,00110	98%	Uzrokuje CF
c.443T>C	p. Ile148Thr	I148T	rs35516286	148	0,00104	88%	Ne izaziva CF
c.349C>T	p.Arg117Cys	R117C	rs77834169	146	0,00103	24%	Uzrokuje CF

Aminokiselinska sekvenca

10	20	30	40	50
MQRSPLEKAS	VVSKLFFSWT	RPILRKGYRQ	RLELSDIYQI	PSVDSADNLS
EKLEREWDRE	LASKKNPKLI	NALRRCFFWR	FMFYGIFLYL	GEVTKAVQPL
LLGRIIASYD	PDNKEERSIA	IYLGIGLCLL	FIVRTLLLHP	AIFGLHHIGM
QMRIAMFSLI	YKKTLKLSSR	VLDKISIGQL	VSLLSNNLNK	FDEGLALAHF
VWIAPLQVAL	LMGLIWELLQ	ASAFCGLGFL	IVLALFQAGL	GRMMMKYRDQ
RAGKISERLV	ITSEMIENIQ	SVKAYCWEEA	MEKMIENLRQ	TELKLTRKAA
YVRYFNSSAF	FFSGFFVVFL	SVLPYALIKG	IILRKIFTTI	SFCIVLRMAV
TRQFPWAVQT	WYDSLGAINK	IQDFLQKQEY	KTLEYNLTTT	EVVMENVTAF
WEEGFGELFE	KAKQNNNNRK	TSNGDDSLFF	SNFSLLGTPV	LKDINFKIER
GQLLAVAGST	GAGKTSLLMV	IMGELEPSEG	KIKHSGRISF	CSQFSWIMPG
TIKENIIFGV	SYDEYRYRSV	IKACQLEEDI	SKFAEKDNIV	LGEGGITLSG
GQRARISLAR	AVYKDADLYL	LDSPFGYLDV	LTEKEIFESC	VCKLMANKTR
ILVTSKMEHL	KKADKILILH	EGSSYFYGTF	SELQNLQPDF	SSKLMGCDSF
DQFSAERRNS	ILTETLHRFS	LEGDAPVSWT	ETKKQSFKQT	GEFGEKRKNS
ILNPINSIRK	FSIVQKTPLQ	MNGIEEDSDE	PLERRLSLVP	DSEQGEAILP
RISVISTGPT	LQARRRQSVL	NLMTHSVNQG	QNIHRKTTAS	TRKVSLAPQA
NLTELDIYSR	RLSQETGLEI	SEEINEEDLK	ECFFDDMESI	PAVTTWNTYL
RYITVHKSLI	FVLIWCLVIF	LAEVAASLVV	LWLLGNTPLQ	DKGNSTHSRN
NSYAVIITST	SSYYVFYIYV	GVADTLLAMG	FFRGLPLVHT	LITVSKILHH
KMLHSVLQAP	MSTLNTLKAG	GILNRFSKDI	AILDDLLPLT	IFDFIQLLLI
VIGAIAVVAV	LQPYIFVATV	PVIVAFIMLR	AYFLQTSQQL	KQLESEGRSP
IFTHLVTSLK	GLWTLRAFGR	QPYFETLFHK	ALNLHTANWF	LYLSTLRWFQ
MRIEMIFVIF	FIAVTFISIL	TTGEGEGRVG	IILTLAMNIM	STLQWAVNSS
IDVDSLMRSV	SRVFKFIDMP	TEGKPTKSTK	PYKNGQLSKV	MIIENSHVKK
DDIWPSGGQM	TVKDLTAKYT	EGGNAILENI	SFSISPGQRV	GLLGRTGSGK
STLLSAFLRL	LNTEGEIQID	GVSWDSITLQ	QWRKAFGVIP	QKVFIFSGTF
RKNLDPYEQW	SDQEIWKVAD	EVGLRSVIEQ	FPGKLDFVLV	DGGCVLSHGH
KQLMCLARSV	LSKAKILLLD	EPSAHLDPVT	YQIIRRTLKQ	AFADCTVILC
EHRIEAMLEC	QQFLVIEENK	VRQYDSIQKL	LNERSLFRQA	ISPSDRVKLF
PHRNSSKCKS	KPQIAALKEE	TEEEVQDTRL

Interakcije

Pokazalo se da regulator transmembranske provodljivosti cistaste fibroze reaguje sa:

Reference

1 2 3 GRCh38: Ensembl release 89: ENSG00000001626 - Ensembl, maj 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000041301 - Ensembl, maj 2017
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↑ Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, et al. (mart 2003). "C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins". Biochemical and Biophysical Research Communications. 302 (3): 454–461. doi:10.1016/S0006-291X(03)00196-7. PMID 12615054.
↑ Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (maj 1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Letters. 427 (1): 103–108. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608. S2CID 20803242.
↑ Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, et al. (septembar 2000). "The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane". The Journal of Biological Chemistry. 275 (35): 27069–27074. doi:10.1074/jbc.M004951200. PMID 10852925.
↑ Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ (juli 1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proceedings of the National Academy of Sciences of the United States of America. 95 (15): 8496–8501. Bibcode:1998PNAS...95.8496H. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706.
↑ Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA (septembar 2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". The Journal of Biological Chemistry. 275 (38): 29539–29546. doi:10.1074/jbc.M004961200. PMID 10893422.
↑ Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, et al. (novembar 1997). "Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms". Nature. 390 (6657): 302–305. Bibcode:1997Natur.390..302N. doi:10.1038/36882. PMID 9384384. S2CID 4395005.

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