Amiloidni prekursorski protein

APP
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1AAP, 1AMB, 1AMC, 1AML, 1BA4, 1BA6, 1BJB, 1BJC, 1BRC, 1CA0, 1HZ3, 1IYT, 1MWP, 1OWT, 1QCM, 1QWP, 1QXC, 1QYT, 1TAW, 1TKN, 1X11, 1Z0Q, 1ZJD, 2BEG, 2BP4, 2FJZ, 2FK1, 2FK2, 2FK3, 2FKL, 2FMA, 2G47, 2IPU, 2LFM, 2LLM, 2LMN, 2LMO, 2LMP, 2LMQ, 2LOH, 2LP1, 2OTK, 2R0W, 2WK3, 2Y29, 2Y2A, 2Y3J, 2Y3K, 2Y3L, 3AYU, 3DXC, 3DXD, 3DXE, 3GCI, 3IFL, 3IFN, 3IFO, 3IFP, 3JTI, 3KTM, 3L33, 3L81, 3MOQ, 3NYL, 3SV1, 3U0T, 3UMH, 3UMI, 3UMK, 4HIX, 1ZE7, 1ZE9, 2LNQ, 2LZ3, 2LZ4, 2M4J, 2M9R, 2M9S, 2MGT, 2MJ1, 2MPZ, 2MVX, 2MXU, 3BAE, 3BKJ, 3JQ5, 3JQL, 3MXC, 3NYJ, 3OVJ, 3OW9, 4JFN, 4M1C, 4MDR, 4NGE, 4OJF, 4ONF, 4ONG, 4PQD, 4PWQ, 4MVI, 4MVK, 4MVL, 4XXD, 5CSZ, 5AMB, 5AEF, 5AM8, 5BUO, 5HOY, 5HOW, 5HOX, 5KK3, 5C67, 2NAO
Identifikatori
Aliasi	APP
Vanjski ID-jevi	OMIM: 104760 MGI: 88059 HomoloGene: 56379 GeneCards: APP
Lokacija gena (čovjek)
Hrom.	Hromosom 21 (čovjek)
Kraj	26,171,128 bp
Lokacija gena (miš)
Hrom.	Hromosom 16 (miš)
Kraj	84,970,654 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• heparin binding; • signaling receptor binding; • acetylcholine receptor binding; • vezivanje iona metala; • vezivanje enzima; • peptidase activator activity; • peptidase inhibitor activity; • GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje sa DNK; • growth factor receptor binding; • PTB domain binding; • serine-type endopeptidase inhibitor activity; • vezivanje identičnih proteina; • transition metal ion binding; • signaling receptor activator activity;
Ćelijska komponenta	• citoplazma; • endozom; • citosol; • trans-Golgi network membrane; • membrana; • cell-cell junction; • sinapsa; • extracellular region; • ciliary rootlet; • spindle midzone; • neuron projection; • rough endoplasmic reticulum; • dendritična kičma; • endosome lumen; • dendritic shaft; • cell surface; • terminal bouton; • Lipidni splav; • Egzosom; • integral component of membrane; • Golđijev aparat; • growth cone; • Nervno-mišićna veza; • receptor complex; • ćelijska membrana; • apical part of cell; • astrocyte projection; • growth cone lamellipodium; • Akson; • nuclear envelope lumen; • clathrin-coated pit; • platelet alpha granule lumen; • integral component of plasma membrane; • main axon; • smooth endoplasmic reticulum; • COPII-coated ER to Golgi transport vesicle; • growth cone filopodium; • GO:0016023 citoplazmatska vezikula; • Vanćelijsko; • Golgi lumen; • perinuklearno područje citoplazme; • early endosome; • endoplasmic reticulum lumen; • Golgi-associated vesicle; • projekcija ćelije; • perikaryon; • presynaptic active zone; • reciklirajući endosom; • jedro; • Sinapsna vezikula;
Biološki proces	• cellular response to nerve growth factor stimulus; • amyloid fibril formation; • negative regulation of neuron differentiation; • neuromuscular process controlling balance; • protein phosphorylation; • regulation of epidermal growth factor-activated receptor activity; • cellular copper ion homeostasis; • neuron projection development; • cellular response to cAMP; • suckling behavior; • GO:0097285 apoptoza; • locomotory behavior; • adult locomotory behavior; • positive regulation of mitotic cell cycle; • axo-dendritic transport; • GO:0001306 response to oxidative stress; • mRNA polyadenylation; • collateral sprouting in absence of injury; • ionotropic glutamate receptor signaling pathway; • Notch signaling pathway; • negative regulation of peptidase activity; • smooth endoplasmic reticulum calcium ion homeostasis; • synaptic assembly at neuromuscular junction; • neuron remodeling; • dendrite development; • extracellular matrix organization; • cholesterol metabolic process; • mating behavior; • cellular response to norepinephrine stimulus; • nervous system development; • Ćelijska adhezija; • response to lead ion; • Regulacija ekspresije gena; • positive regulation of G2/M transition of mitotic cell cycle; • axon midline choice point recognition; • visual learning; • Endocitoza; • axonogenesis; • regulation of multicellular organism growth; • platelet degranulation; • positive regulation of peptidase activity; • forebrain development; • regulation of protein binding; • regulation of translation; • regulation of synapse structure or activity; • GO:0006928 cellular process or phenomenon; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • negative regulation of endopeptidase activity; • response to yeast; • antibacterial humoral response; • antifungal humoral response; • Urođeni imunski sistem; • GO:0051636 defense response to Gram-negative bacterium; • GO:0051637 defense response to Gram-positive bacterium; • neuron apoptotic process; • positive regulation of protein phosphorylation; • astrocyte activation involved in immune response; • G protein-coupled receptor signaling pathway; • learning or memory; • Učenje; • negative regulation of cell population proliferation; • response to radiation; • GO:1901313 positive regulation of gene expression; • negative regulation of gene expression; • positive regulation of peptidyl-threonine phosphorylation; • microglia development; • regulation of Wnt signaling pathway; • positive regulation of protein binding; • tumor necrosis factor production; • positive regulation of peptidyl-serine phosphorylation; • positive regulation of phosphorylation; • Posttranslacione modifikacije; • positive regulation of JNK cascade; • astrocyte activation; • regulation of long-term neuronal synaptic plasticity; • regulation of peptidyl-tyrosine phosphorylation; • synapse organization; • kognitivna funkcija; • positive regulation of DNA-binding transcription factor activity; • positive regulation of NF-kappaB transcription factor activity; • positive regulation of astrocyte activation; • positive regulation of ERK1 and ERK2 cascade; • cellular response to copper ion; • cellular response to manganese ion; • modulation of excitatory postsynaptic potential; • regulation of spontaneous synaptic transmission; • negative regulation of long-term synaptic potentiation; • positive regulation of long-term synaptic potentiation; • positive regulation of NIK/NF-kappaB signaling; • positive regulation of amyloid-beta formation; • positive regulation of microglial cell activation; • cellular response to amyloid-beta; • negative regulation of low-density lipoprotein receptor activity; • regulation of presynapse assembly; • positive regulation of amyloid fibril formation; • neuron projection maintenance; • positive regulation of signaling receptor activity; • regulation of NMDA receptor activity; • positive regulation of T cell migration; • response to interleukin-1; • positive regulation of glycolytic process;
	Izvori:Amigo / QuickGO
Ortolozi
	351
	11820
	ENSG00000142192
	ENSMUSG00000022892
	P05067
	P12023
NM_201414; NM_000484; NM_001136016; NM_001136129; NM_001136130;
	NM_001136131; NM_001204301; NM_001204302; NM_001204303; NM_201413; NM_001385253
	NM_001198823; NM_001198824; NM_001198825; NM_001198826; NM_007471
NP_000475; NP_001129488; NP_001129601; NP_001129602; NP_001129603;
	NP_001191230; NP_001191231; NP_001191232; NP_958816; NP_958817
	NP_001185752; NP_001185753; NP_001185754; NP_001185755; NP_031497
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

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

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

Dužina polipeptidnog lanca je 770 aminokiselina, a molekulska težina 86.943 Da.^[5]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

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

Metal-vezujući domen APP sa vezanim bakarnin ionom. Bočni lanac dva ostatka histidina i jednog tirozina koji imaju ulogu u koordinaciji metala prikazani su u vezanim Cu(I), vezanim Cu(II) i nevezanim konformacijama, koji se razlikuju samo po malim promjenama u orijentaciji.

Vanćelijski E2 domen, dimerna upredena zavojnica i jedan od najkonzerviranijih regiona proteina od Drosophila do ljudi. Smatra se da ovaj domen, koji liči na strukturu spektrina, veže heparan-sulfatne proteoglikane.^[23]

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 poput: domen sličan faktoru rasta,^[26], domena koja veže bakar^[27] kompletna E1 domena^[24] i domen E2.^[23]

Funkcija

Iako je izvorna biološka uloga APP-a od očiglednog interesa za istraživanje Alzheimerove bolesti, temeljito razumijevanje je ostalo nedostižno.

Formiranje i popravak sinapsi

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

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

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

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

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

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]

Reference

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Vanjski linkovi

Commons logo

Commons ima datoteke na temu: Amiloidni prekursorski protein

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.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000142192 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000022892 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[UniProt-5] "Amyloid-beta precursor protein". Pristupljeno 10. 1. 2021.

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