CCR5
![](http://upload.wikimedia.org/wikipedia/commons/thumb/c/c7/HIV_attachment.gif/310px-HIV_attachment.gif)
1 – gp120 virusni protein se veže za CD4.
2 – gp120 varijabilna petlja se pričvršćuje na koreceptor, bilo CCR5 ili CXCR4.
3 – HIV ulazi u ćeliju.
C-C hemokinski receptor tip 5, znan i kao CCR5 ili CD195, je protein na površini leukocita, uključen imunski sistem, kao receptor za hemokine.[5]
Kod ljudi, određene populacije naslijedile su mutaciju Delta 32, što je rezultiralo delecijom dijela gena CCR5. Homozigot ni nositelji ove mutacije otporni su na M-tropske sojeve HIV-1 infekcije.[6][7][8][9][10][11]
Funkcija
[uredi | uredi izvor]Protein CCR5 pripada porodici beta hemokinskih receptora, integralnih membranskih proteina.[12][13] To je G-protein spregnuti receptor[12] koji djeluje kao hemokinski receptor u CC hemokinskoj grupi.
CCR5-u srodni ligandi uključuju CCL3, CCL4 (poznat i kao MIP 1α i 1β ) i CCL3L1.[14][15] CCR5 nadalje komunicira sa CCL5 (hemotaksijskim citokinskim proteinom, poznatim i kao RANTES).[14][16][17]
CCR5 je pretežno izražen na T-ćelijama, makrofagima, dendritskim ćelijama, eozinofiliima, mikrogliji i subpopulacijama ćelija karcinoma dojke ili prostate.[18][19] Ekspresija CCR5 selektivno se inducira tokom procesa transformacije raka i ne ispoljava se u normalnim epitelnim ćelijama 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 ubijenih hemoterapijom.[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]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/d3/CCR5_Primary_Protein_Sequence.png/220px-CCR5_Primary_Protein_Sequence.png)
HIV
[uredi | uredi izvor]HIV-1 najčešće koristi hemokinske receptore CCR5 i/ili CXCR4 kao koreceptor za ulazak u ciljne imunske ćelije.[23] Ovi receptori nalaze se na površini imunskih ćelija domaćina, čime daju mogućnost ulaska virusa HIV-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-1 env gene: the Gp120 external subunit and the Gp41 transmembrane subunit.[24] Ova glikoproteinska struktura omotača raspoređena je u strukturu sličnu klasi koja se nalazi na površini viriona i sastoji se od trimera Gp120-Gp41 heterodimera.[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. Normalni ligandi za ovaj receptor, RANTES, MIP-1β i MIP-1α, sposobni su suzbiti HIV-1 infekciju in 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, zvani CCR5 antagonist receptora, dizajnirani su da ometaju vezanje između proteinskog omotača Gp120 i HIV koreceptora CCR5. Ovi eksperimentalni lijekovi uključuju PRO140 (CytoDyn), Vicriviroc (ispitivanja faze III otkazana su u julu 2010.) (Schering plug, Aplaviroc (GW-873140) (GlaxoSmithKline) i Maraviroc (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, pod selekcijskim pritiskom HIV razviti u upotrebu drugog koreceptora. Međutim, ispitivanje virusne rezistencije na AD101, molekulski antagonista CCR5, 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 njegov citoplazmatski rep), što je rezultiralo neovisnošću CD4 bez potrebe CCR5 i/ili CXCR4 kao ulaznog puta.[30]
Kancer
[uredi | uredi izvor]Ekspresija CCR5 inducira se u epitelnim ćelijama dojke i prostate, nakon transformacije. Indukcija ekspresije CCR5 promovira ćelijsku invaziju, migraciju i metastaze. 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 na moždani 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 veze neurona. 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) je alel CCR5-a.
CCR5-Δ32
[uredi | uredi izvor]CCR5-Δ32 (ili CCR5-D32 ili CCR5 delta 32) je alel CCR5-a.[35][36]
CCR5 Δ32 je delecija u paru od 32 baze, koja uvodi prerano stop kodon u CCR5 receptorski lokus, što rezultira nefunkcionalnim receptorom.[37][38] CCR5 is required for M-tropic HIV-1 virus entry.[39] Homozigotne osobe (označeno sa Δ32 / Δ32) za CCR5 Δ32 ne ispoljavaju funkcionalne CCR5 receptore na ćelijskim površinama i otporni su na infekciju HIV-1-om, uprkos višestrukoj izloženosti visokom riziku. Heterozigotne (+ / Δ32) za mutantni alel imaju 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 reduced viral loads and a 2-3-year-slower progression to AIDS relative 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 from NCBI Gene Database
- Crystal Structure of the CCR5 Chemokine Receptor A 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 s originala, 18. 1. 2021. Pristupljeno 16. 3. 2021.
- HuGENavigator literature on HIV Infections and CCR5 from 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.
- HIVcoPred A server for prediction of HIV coreceptor usage (CCR5). PLoS ONE 8(4): e61437
- Lokacija ljudskog genoma CCR5 i stranica sa detaljima o genu CCR5 u UCSC Genome Browseru.
- P51681