CCR5
C-C hemokinski receptor tip 5,znan i kaoCCR5iliCD195,jeproteinna površinileukocita,uključenimunski sistem,kaoreceptorzahemokine.[5]
Kod ljudi, određene populacije naslijedile su mutacijuDelta 32,što je rezultiralodelecijomdijela gena CCR5.Homozigotni nositelji ove mutacije otporni su naM-tropske sojeveHIV-1 infekcije.[6][7][8][9][10][11]
Funkcija
[uredi|uredi izvor]Protein CCR5 pripada porodicibeta hemokinskih receptora,integralnih membranskih proteina.[12][13]To jeG-protein spregnuti receptor[12]koji djeluje kaohemokinski receptoruCC hemokinskoj grupi.
CCR5-u srodniligandiuključujuCCL3,CCL4(poznat i kao MIP 1αi 1β) iCCL3L1.[14][15]CCR5 nadalje komunicira saCCL5(hemotaksijskimcitokinskimproteinom, poznatim i kao RANTES).[14][16][17]
CCR5 je pretežnoizražennaT-ćelijama,makrofagima,dendritskimćelijama,eozinofiliima,mikroglijii subpopulacijama ćelijakarcinoma dojkeiliprostate.[18][19]Ekspresija CCR5 selektivno se inducira tokom procesa transformacije raka i ne ispoljava se u normalnimepitelnimćelijama dojke ili prostate. Otprilike 50% ljudskog karcinoma dojke ispoljilo je CCR5, prvenstveno kod trostruko negativnog karcinoma dojke.[18]CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR5, suggesting that CCR5 may function as a new therapeutic target.[18][19][20]Nedavna istraživanja sugeriraju da se CCR5 eksprimira u podgrupi ćelija karcinoma sa karakteristikama matičnih ćelija karcinoma, za koje je poznato da podstiču terapijsku rezistenciju, te da su inhibitori CCR5 povećali broj ćelija trenutno ubijenihhemoterapijom.[21]Vjerovatno je da CCR5 ima ulogu u upalnom odgovoru na infekciju, iako njegova tačna uloga u normalnoj imunskoj funkciji nije jasna. Regije ovog proteina su takođe ključne za vezanje hemokin-liganda, kao funkcionalni odgovor receptora i aktivnost koreceptora za HIV.[22]
HIV
[uredi|uredi izvor]HIV-1najčešće koristi hemokinske receptore CCR5 i/iliCXCR4kaokoreceptorza ulazak u ciljne imunske ćelije.[23]Ovi receptori nalaze se na površini imunskih ćelija domaćina, čime daju mogućnost ulaskavirusaHIV-1 da zarazi ćeliju.[24]The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.[24]The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1envgene: the Gp120 external subunit and the Gp41 transmembrane subunit.[24]Ovaglikoproteinskastruktura omotača raspoređena je u strukturu sličnu klasi koja se nalazi na površini viriona i sastoji se od trimera Gp120-Gp41heterodimera.[24]The Gp120 envelope protein is a chemokine mimic. Iako mu nedostaje jedinstvena struktura kemokina, i dalje je sposoban da se veže za CCR5 i CXCR4 hemokinske receptore. Tokom HIV-1 infekcije, podjedinica glikoproteinskog omotača Gp120 veže se za glikoprotein CD4 i koreceptor za HIV-1, eksprimiran na ciljnoj ćeliji, formirajući heterotrimerni kompleks. Stvaranje ovog kompleksa stimulira oslobađanje fuzogenog peptida, zbog čega se virusna membrana spaja s membranom ciljanih ćelija domaćina. Budući da vezanje samo za CD4 ponekad može rezultirati oslobađanjem gp120, gp120 se mora dalje vezati za koreceptor CCR5 kako bi fuzija nastavila. Tirozin-sulfatni amino-kraj ovog ko-receptora je "bitna odrednica" vezanja za gp120 glikoprotein.[25]Koreceptor također prepoznaje V1-V2 regiju gp120 i premošćujući sloj (antiparalelni, 4-lančani β sloj koji povezuje unutrašnji i vanjki domen gp120). Drška V1-V2 može uticati na "upotrebu koreceptora putem peptidnog sastava, kao i stupnjem N-vezane glikozilacije". Međutim, za razliku od V1-V2, petlja V3 vrlo je varijabilna i stoga je najvažnija odrednica specifičnosti ko-receptora. Normalniligandiza ovaj receptor,RANTES,MIP-1βiMIP-1α,sposobni su suzbiti HIV-1 infekcijuin vitro.Kod osoba zaraženih HIV-om, virusi koji koriste CCR5 su pretežni tipovi izolirani tokom ranih stadija virusne infekcije,[26]što sugerira da ovi virusi mogu imati selektivnu prednost tokom prenosa ili akutne faze bolesti. Štaviše, najmanje polovina svih zaraženih osoba, u toku infekcije ima samo viruse koji koriste CCR5.
CCR5 je primarni ko-receptor koji gp120 koristi uzastopno sa CD4. Rezultat ovog vezanja je da se gp41, drugi proteinski proizvod gp160, oslobodi iz svoje metastabilne konformacije i ubaci u membranu ćelije domaćina. Iako nije potvrđeno, vezanje gp120-CCR5 uključuje dva ključna koraka: (1) tirozin-sulfatni amino kraj ovog koreceptora je "bitna odrednica" vezanja za gp120 i (2) nakon koraka 1, mora postojati uzajamno djelovanje (sinergija, međusobna komunikacija) između gp120 i CCR5 transmembranskih domena.
CCR5 je neophodan za širenje R5-soja virusa HIV-1.[27]Poznavanje mehanizma kojim ovaj soj HIV-1 posreduje infekciju podstaknulo je istraživanje u razvoju terapijskih intervencija za blokiranje funkcije CCR5.[28]Brojni novi eksperimentalni HIV lijekovi, zvaniCCR5 antagonist receptora,dizajnirani su da ometaju vezanje između proteinskog omotača Gp120 i HIV koreceptora CCR5. Ovi eksperimentalni lijekovi uključujuPRO140(CytoDyn),Vicriviroc(ispitivanja faze III otkazana su u julu 2010.) (Schering plug,Aplaviroc(GW-873140) (GlaxoSmithKline) iMaraviroc(UK-427857) (Pfizer). FDA je odobrila za upotrebu Maraviroc u avgustu 2007. Za kliničku upotrebu, FDA ga je jedino do sada odobrila, čime je postao prvi inhibitor CCR5. Problem ovog pristupa je tšto, iako je CCR5 glavni koreceptor kojim HIV zaražava ćelije, nije jedini takav koreceptor. Moguće je da će se, podselekcijskim pritiskomHIV razviti u upotrebu drugog koreceptora. Međutim, ispitivanje virusne rezistencije na AD101, molekulskiantagonistaCCR5, pokazalo je da rezistentni virusi nisu prešli na drugi koreceptor (CXCR4), ali su ustrajali u upotrebi CCR5. Vezali su se za alternativne domene CCR5 ili na receptor sa većim afinitetom. Međutim, budući da još uvijek postoji još jedan koreceptor, vjerovatno je da nedostatak gena CCR5 ne čini imunost na virus. Virus također i dalje ima pristup CD4. Za razliku od CCR5, koji nije potreban (što dokazuju oni koji žive zdravim životom čak i kad im nedostaje gen kao rezultat mutacije delta32), CD4 je presudan u imunskom odbrambenom sistemu tijela.[29]Čak i bez dostupnosti bilo koreceptora (čak i CCR5), virus i dalje može napasti ćelije, ako bi gp41 prošao kroz izmjenu (uključujući njegovcitoplazmatskirep), što je rezultiralo neovisnošću CD4 bez potrebe CCR5 i/ili CXCR4 kao ulaznog puta.[30]
Kancer
[uredi|uredi izvor]Ekspresija CCR5 inducira se uepitelnimćelijama dojke i prostate, nakon transformacije. Indukcija ekspresije CCR5 promovira ćelijsku invaziju, migraciju imetastaze.Indukcija metastaza pak uključuje usmjeravanje na metastatsko mjesto. Pokazalo se da CCR5 inhibitori, uključujući Maraviroc i Leronlimab, blokiraju metastazu na plućnim ćelijskim linijaama karcinoma dojke. U pretkliničkim ispitivanjima imunih miševa, CCR5 inhibitori blokirali su metastaze u kostima i mozgu. CCR5 inhibitori također smanjuju infiltraciju makrofaga povezanih s tumorom.[31]Studija faze 1 kliničkog ispitivanja inhibitora CCR5 kod teško liječenih pacijenata sa metastatskim karcinomom debelog crijeva pokazala je objektivan klinički odgovor i smanjenje metastatskog opterećenja tumora.[32]
Mozak
[uredi|uredi izvor]Povećani nivoi CCR5 dio su upalnog odgovora namoždani udar.Blokiranje CCR5 lijekom Maraviroc (lijek odobren za HIV) može poboljšati oporavak nakon udara.[33][34]
U mozgu u razvoju, hemokini poput CCR5 utiču na migracije i vezeneurona.Nakon moždanog udara, čini se da smanjuju broj mjesta povezivanja na neuronima u blizini oštećenja.
CCR5-Δ32
[uredi|uredi izvor]CCR5-Δ32 (ili CCR5-D32 ili CCR5 delta 32) jealelCCR5-a.
CCR5-Δ32
[uredi|uredi izvor]CCR5-Δ32 (ili CCR5-D32 ili CCR5 delta 32) jealelCCR5-a.[35][36]
CCR5 Δ32 jedelecijau paru od 32 baze, koja uvodi preranostop kodonu CCR5 receptorski lokus, što rezultira nefunkcionalnim receptorom.[37][38]CCR5 is required for M-tropic HIV-1 virus entry.[39]Homozigotneosobe (označeno sa Δ32 / Δ32) za CCR5 Δ32 ne ispoljavaju funkcionalne CCR5 receptore na ćelijskim površinama i otporni su na infekcijuHIV-1-om, uprkos višestrukoj izloženosti visokom riziku.Heterozigotne(+ / Δ32) za mutantnialelimaju više od 50% smanjenje funkcionalnih CCR5 receptora na površinama ćelija, zbog dimerizacije između mutiranih i divljih receptora, koji ometaju transportom CCR5 na površinu ćelije.[40]Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reducedviral loadsand a 2-3-year-slower progression toAIDSrelative to wild types.[37][39][41]Heterozigoznost za ovaj mutirani alel također je pokazala da poboljšava odgovor na virus, na antiretrovirusni tretman.[42]U Evropi, CCR5 Δ32 ima učestalost alela (heterozigota) od 10%, a frekvenciju homozigota od 1%.
Nedavna istraživanja pokazuju da CCR5 Δ32 poboljšava kogniciju i pamćenje. U 2016. istraživanja su pokazala da je uklanjanje gena CCR5 miševa značajno poboljšalo njihovo pamćenje.[43]CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.[44]
Također pogledajte
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Vanjski linkovi
[uredi|uredi izvor]- CCR5 - C-C motif chemokine receptor 5 (gene/pseudogene) - Homo sapiens (human)Information fromNCBI Gene Database
- Crystal Structure of the CCR5 Chemokine ReceptorA rotatable, zoomable 3-D image from rcsb.org
- Video and text from a PBS documentary about the discovery of CCR5
- "Chemokine Receptors: CCR5".IUPHAR Database of Receptors and Ion Channels.International Union of Basic and Clinical Pharmacology. Arhivirano soriginala,18. 1. 2021.Pristupljeno 16. 3. 2021.
- HuGENavigator literature on HIV Infections and CCR5from Centers for Disease Control and Prevention - (note, authors may not be CDC employees, and there is no public domain notice on the page, so this cannot be assumed to be public domain)
- Schering-Plough Initiates Phase III Studies with CCR5-Vicriviroc in Treatment- Experienced HIV Patients.
- HIVcoPredA server for prediction of HIV coreceptor usage (CCR5).PLoS ONE 8(4): e61437
- Lokacija ljudskog genomaCCR5i stranica sa detaljima o genuCCR5uUCSC Genome Browseru.
- P51681