Amiloidni prekursorski protein
Amiloidni prekursorski protein (APP) je integralni membranski protein eksprimiran u mnogim tkivima i koncentriran u sinapsama neurona. Funkcioniše kao receptor ćelijske površine[5] i impliciran je kao regulator formiranja sinapsi,[6] plastičnost,[7] antimikrobu aktivnost,[8] i eksport gvožđa.[9] Kodiran je genom APP i reguliran prezentacijom supstrata.[10] APP je najpoznatiji kao prekursorska molekula čija proteoliza stvara amiloid beta (Aβ), polipeptid koji sadrži 37 do 49 aminokiselinskih ostataka, čiji amiloidni vlaknasti oblik je primarna komponenta amiloidnog plaka koji se nalazi u mozgu pacijenata s Alzheimerovom bolešću.
Genetika
[uredi | uredi izvor]Amiloid-beta prekursorski protein je drevna i visoko konzervirani protein.[11] U ljudi, gen APP nalazi se na hromosomu 21 i sadrži 18 egzona koji obuhvataju 290 kilobaza.[12][13] Kod ljudi primijećeno je nekoliko alternativno prerađenih izoformi APP-a, u rasponu dužine od 639 do 770 aminokiselina, s određenim izoformama prvenstveno eksprimiranim u neuronima; promjene u neuronskom omjeru ovih izoformi povezane su s Alzhheimerovom bolešću.[14] Homologni proteini identifikovani su u drugim organizmima kao što su u rodu Drosophila (vinske mušice), C. elegans (oble gliste),[15] i svi sisari.[16] Amiloidna beta regija proteina, koja se nalazi u domenu koji se prostire na membrani, nije dobro konzervirana među vrstama i nema očiglednu vezu sa biološkim funkcijama APP-a u nativnom stanju.[16]
Mutacije u kritičnim regijama amiloidnog prekursora proteina, uključujući regiju koja stvara amiloid-beta (Aβ), uzrokuju porodičnu osjetljivost na Alzheimerovu bolest.[17][18][19][20] Naprimjer, otkriveno je da nekoliko mutacija izvan Aβ regije povezanih s porodičnom Alzhejmerovom bolešću dramatično povećava proizvodnju Aβ.[21]
Mutacija A673T u APP genu štiti od Alzheimerove bolesti. Ova zamjena je u blizini mjesta cijepanja beta sekretaze i rezultira smanjenjem od 40% u stvaranju beta amiloida in vitro.[22]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 770 aminokiselina, a molekulska težina 86.943 Da.[5]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MLPGLALLLL | AAWTARALEV | PTDGNAGLLA | EPQIAMFCGR | LNMHMNVQNG | ||||
KWDSDPSGTK | TCIDTKEGIL | QYCQEVYPEL | QITNVVEANQ | PVTIQNWCKR | ||||
GRKQCKTHPH | FVIPYRCLVG | EFVSDALLVP | DKCKFLHQER | MDVCETHLHW | ||||
HTVAKETCSE | KSTNLHDYGM | LLPCGIDKFR | GVEFVCCPLA | EESDNVDSAD | ||||
AEEDDSDVWW | GGADTDYADG | SEDKVVEVAE | EEEVAEVEEE | EADDDEDDED | ||||
GDEVEEEAEE | PYEEATERTT | SIATTTTTTT | ESVEEVVREV | CSEQAETGPC | ||||
RAMISRWYFD | VTEGKCAPFF | YGGCGGNRNN | FDTEEYCMAV | CGSAMSQSLL | ||||
KTTQEPLARD | PVKLPTTAAS | TPDAVDKYLE | TPGDENEHAH | FQKAKERLEA | ||||
KHRERMSQVM | REWEEAERQA | KNLPKADKKA | VIQHFQEKVE | SLEQEAANER | ||||
QQLVETHMAR | VEAMLNDRRR | LALENYITAL | QAVPPRPRHV | FNMLKKYVRA | ||||
EQKDRQHTLK | HFEHVRMVDP | KKAAQIRSQV | MTHLRVIYER | MNQSLSLLYN | ||||
VPAVAEEIQD | EVDELLQKEQ | NYSDDVLANM | ISEPRISYGN | DALMPSLTET | ||||
KTTVELLPVN | GEFSLDDLQP | WHSFGADSVP | ANTENEVEPV | DARPAADRGL | ||||
TTRPGSGLTN | IKTEEISEVK | MDAEFRHDSG | YEVHHQKLVF | FAEDVGSNKG | ||||
AIIGLMVGGV | VIATVIVITL | VMLKKKQYTS | IHHGVVEVDA | AVTPEERHLS | ||||
KMQQNGYENP | TYKFFEQMQN |
Struktura
[uredi | uredi izvor]U APP sekvenci je identifikovan niz različitih, uglavnom nezavisno-sklopljenih strukturnih domena. Vanćelijska regija, mnogo veću od unutarćelijske regije, podijeljena je na E1 i E2 domene, povezane kiselim domenom (AcD); E1 sadrži dva poddomena uključujući domen sličan faktoru rasta (GFLD) i bakar-vezujući domen (CuBD) koji međusobno čvrsto djeluju.[24] Domen inhibitora serinske proteaze, odsutan iz izoforme različito eksprimirane u mozgu, nalazi se između kiselog područja i E2 domena.[25] Kompletna kristalna struktura APP-a još nije riješena; međutim, pojedinačni domeni su uspješno kristalizirani, domen sličan faktoru rasta,[26]
Neke riječi u sljedećem pasusu trebaju prijevod na bosanski jezik. |
the copper-binding domain,[27] the complete E1 domain[24] i domen E2.[23]
Funkcija
[uredi | uredi izvor]Iako je izvorna biološka uloga APP-a od očiglednog interesa za istraživanje Alzheimerove bolesti, temeljito razumijevanje je ostalo nedostižno.
Formiranje i popravak sinapsi
[uredi | uredi izvor]Najvažnija uloga APP-a je u m formiranju i popravljanju sinapsi;[6] njegova ekspresija je nadregulirana tokom neuronske diferencijacije i nakon nervne ozljede. Uloge u ćelijskoj signalizaciji, dugotrajnoj potenciaciji i ćelijskoj adheziji predložene su i podržane još ograničenim istraživanjem.[16] Konkretno, sličnosti u posttranslacijskoj obradi pozvali su na poređenja sa signalnom ulogom površinskog receptorskog proteina Notch.[28]
APP nokaut-miševi su održivi i imaju relativno male fenotipske efekte, uključujući oštećeno dugotrajno potenciranje i gubitak pamćenja bez općeg gubitka neurona.[29] S druge strane, zabilježeno je da transgeni miševi s povećanom ekspresijom APP-a pokazuju smanjenu dugotrajnu potencijaciju.[30]
Logičan zaključak je da bi, budući da se Aβ prekomjerno akumulira kod Alzheimerove bolesti, njegov prekursor, APP, također bio povišen. Međutim, tijela neuronskih ćelija sadrže manje APP kao funkciju njihove blizine amiloidnim plakovima.[31] Podaci pokazuju da je ovaj deficit u APP-u posljedica pada proizvodnje, a ne povećanja katalize. Gubitak APP neurona može uticati na fiziološke deficite koji doprinose demenciji.
Somatska rekombinacija
[uredi | uredi izvor]U neuronima ljudskog mozga, u genu koji kodira APP česta je somatska rekombinacija.[32] Neuroni osoba sa sporadičnom Alzheimmerovom bolešću pokazuju veću raznolikost gena APP zbog somatske rekombinacije nego neuroni zdravih osoba.[32]
Anterogradni neuronski transport
[uredi | uredi izvor]Molekule sintetizirane u ćelijskim tijelima neurona moraju se prenijeti prema van do distalnih sinapsi. Ovo se postiže putem brzog anterogradnog transporta. Utvrđeno je da APP može posredovati u interakciji između tereta i kinezina i na taj način olakšati ovaj transport. Konkretno, kratka peptidna sekvenca od 15 aminokiselina sa citoplazmatskog karboksi-terminala neophodna je za interakciju sa motornim proteinom.[33]
Dodatno, pokazalo se da je interakcija između APP i kinezina specifična za peptidnu sekvencu APP-a.[34] U nedavnom eksperimentu koji je uključivao transport obojenih kuglica, kontrole su konjugirane na jednu aminokiselinu, glicin, tako da pokazuju istu terminalnu grupu karboksilne kiseline kao APP bez intervencije gorepomenute 15-aminokiselinske sekvenca. Kontrolne kuglice nisu bile pokretne, što je pokazalo da terminalni COOH dio peptida nije dovoljan da posreduje u transportu.
Eksport gvožđa
[uredi | uredi izvor]Drugačiju perspektivu na Alzheimerovu bolest otkriva studija na mišu koja je otkrila da APP posjeduje feroksidaznu aktivnost sličnu ceruloplazminu, olakšavajući metabolizam i eksport gvožđa kroz interakciju sa feroportinom; čini se da je ova aktivnost blokirana cinkom zarobljenim akumuliranim Aβ kod Alzheimerove bolesti.[9] Pokazalo se da jednonukleotidni polimorfizam u 5' UTR-u APP iRNK može poremetiti njegovu translaciju.[35]
Hipoteza da APP ima aktivnost feroksidaze u domenu E2 i olakšava eksport Fe(II) je vjerovatno netačna jer predloženo mjesto feroksidaze APP u E2 domenu nema aktivnost feroksidaze.[36][37]
Kako APP ne posjeduje aktivnost feroksidaze unutar svog E2 domena, mehanizam APP-moduliranog efluksa gvožđa iz feroportina bio je pod kontrolom. Jedan model sugerira da APP djeluje na stabilizaciju proteina feroportina koji izlijeva gvožđe u ćelijskim plazmamembranama, čime se povećava ukupan broj feroportinskih molekula na membrani. Ovi transporteri gvožđa se zatim mogu aktivirati poznatim feroksidazama sisara (tj. ceruloplazminom ili hefestinom).[38]
Hormonska regulacija
[uredi | uredi izvor]Amiloid-β prekursorski protein (AβPP), i sve povezane sekretaze, eksprimiraju se u ranoj fazi razvoja i imaju ključnu ulogu u endokrinologiji reprodukcije – uz diferencijalnu obradu AβPP sekretazama koje regulišu proliferaciju ljudskih embrionskih matičnih ćelija (hESC) kao i njihovu diferencijaciju u nervne prekursorske ćelije (NPC). Hormon trudnoće ljudski horionski gonadotropin (hCG) povećava ekspresiju AβPP [39] i proliferaciju hESC-a, dok progesteron usmjerava preradu AβPP prema neamiloidogenom putu, koji promovira diferencijaciju hESC-a u NPC.[40][41][42]
AβPP i njegovi proizvodi cijepanja ne promovišu proliferaciju i diferencijaciju postmitotskih neurona; prije će biti da prekomjerna ekspresija bilo divljeg tipa ili mutantnog AβPP u postmitotskim neuronima inducira apoptozhnu smrt nakon njihovog ponovnog ulaska u ćelijski ciklus.[43] Pretpostavlja se da je gubitak spolnih steroida (uključujući progesteron), ali i povećanje razine luteinizirajućeg hormona, ekvivalent hCG-a za odrasle, nakon menopauze i tokom andropauze pokreće proizvodnju amiloida-β[44] i ponovni ulazak postmitotskih neurona u ćelijski ciklus.
Interakcije
[uredi | uredi izvor]Pokazalo se da protein prekursor amiloida reaguje sa:
APP stupa u interakciju i s reelinom, proteinom koji je uključen u brojne poremećaje mozga, uključujući Alzheimerovu bolest.[65]
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Vanjski linkovi
[uredi | uredi izvor]- GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease
- Amyloid Protein Precursor na US National Library of Medicine Medical Subject Headings (MeSH)
- Entrez Gene: APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
- Lokacija ljudskog genoma APP i stranica sa detaljima o genu APP u UCSC Genome Browseru.