MAPT

MAPT
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1I8H, 4GLR, 2ON9, 3OVL, 4E0M, 4E0N, 4E0O, 4FL5, 4NP8, 2MZ7, 4TQE, 4Y5I, 4Y32, 5DMG, 4Y3B, 5HF3, 5E2W, 5E2V
Identifikatori
Aliasi	MAPT
Vanjski ID-jevi	OMIM: 157140 MGI: 97180 HomoloGene: 74962 GeneCards: MAPT
Lokacija gena (čovjek) Hrom. Hromosom 17 (čovjek)[1] Bend 17q21.31 Početak 45,894,527 bp[1] Kraj 46,028,334 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11 67.79 cM|11 E1 Početak 104,231,390 bp[2] Kraj 104,332,090 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • apolipoprotein binding • SH3 domain binding • vezivanje tubulina • GO:0001948, GO:0016582 vezivanje za proteine • lipoprotein particle binding • vezivanje enzima • vezivanje sa DNK • actin binding • microtubule binding • dynactin binding • receptor ligand activity • protein phosphatase 2A binding • Hsp90 protein binding • minor groove of adenine-thymine-rich DNA binding • double-stranded DNA binding • single-stranded DNA binding • vezivanje sa RNK • protein kinase binding • protein-macromolecule adaptor activity • phosphatidylinositol binding • vezivanje identičnih proteina • protein homodimerization activity • sequence-specific DNA binding • chaperone binding • histone-dependent DNA binding • microtubule lateral binding • phosphatidylinositol bisphosphate binding Ćelijska komponenta • citoplazma • cell body • projekcija ćelije • nuclear periphery • growth cone • neurofibrillary tangle • ćelijska membrana • tubulin complex • dendrit • cytoplasmic ribonucleoprotein granule • citoskelet • jedro • citosol • Mikrotubula • microtubule associated complex • membrana • nuclear speck • Akson • somatodendritic compartment • soma • axon cytoplasm • extracellular region • intracellular anatomical structure • mitohondrija • microtubule cytoskeleton • axolemma • neuron projection • dendritična kičma • main axon • Lipidni splav • glial cell projection Biološki proces • generation of neurons • regulation of autophagy • regulation of microtubule polymerization • positive regulation of microtubule polymerization • positive regulation of axon extension • microtubule cytoskeleton organization • microglial cell activation • activation of cysteine-type endopeptidase activity involved in apoptotic process • GO:0072468 Transdukcija signala • Memorija • negative regulation of mitochondrial membrane potential • axonal transport of mitochondrion • cytoplasmic microtubule organization • neuron projection development • positive regulation of superoxide anion generation • negative regulation of kinase activity • cellular response to heat • astrocyte activation • intracellular distribution of mitochondria • synapse organization • regulation of calcium-mediated signaling • protein complex oligomerization • plus-end-directed organelle transport along microtubule • regulation of mitochondrial fission • negative regulation of mitochondrial fission • axonal transport • regulation of cellular response to heat • positive regulation of neuron death • positive regulation of protein localization to synapse • neurofibrillary tangle assembly • negative regulation of establishment of protein localization to mitochondrion • positive regulation of diacylglycerol kinase activity • regulation of response to DNA damage stimulus • internal protein amino acid acetylation • cell-cell signaling • response to lead ion • regulation of signaling receptor activity • negative regulation of gene expression • rRNA metabolic process • central nervous system neuron development • regulation of microtubule polymerization or depolymerization • regulation of chromosome organization • stress granule assembly • GO:0072353 cellular response to reactive oxygen species • microtubule polymerization • regulation of synaptic plasticity • axon development • regulation of microtubule cytoskeleton organization • supramolecular fiber organization • regulation of long-term synaptic depression • positive regulation of protein localization • negative regulation of tubulin deacetylation • amyloid fibril formation • cellular response to nerve growth factor stimulus • cellular response to brain-derived neurotrophic factor stimulus Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	4137	17762
Ensembl	ENSG00000186868 ENSG00000276155 ENSG00000277956	ENSMUSG00000018411
UniProt	P10636	P10637
RefSeq (mRNK)	NM_001123066 NM_001123067 NM_001203251 NM_001203252 NM_005910 NM_016834 NM_016835 NM_016841 NM_001377265 NM_001377266 NM_001377267 NM_001377268	NM_001038609 NM_010838 NM_001285454 NM_001285455 NM_001285456
RefSeq (bjelančevina)	NP_001116538 NP_001116539 NP_001190180 NP_001190181 NP_005901 NP_058518 NP_058519 NP_058525 NP_001364194 NP_001364195 NP_001364196 NP_001364197	NP_001033698 NP_001272383 NP_001272384 NP_001272385 NP_034968 NP_001390904 NP_001390905 NP_001390906 NP_001390907 NP_001390908 NP_001390909 NP_001390910 NP_001390911 NP_001390912 NP_001390913 NP_001390916 NP_001390919 NP_001390921 NP_001390923 NP_001390925 NP_001390927 NP_001390928 NP_001390931 NP_001390933 NP_001390934 NP_001390935 NP_001390939 NP_001390940 NP_001390941 NP_001390943 NP_001390944 NP_001390945
Lokacija (UCSC)	Chr 17: 45.89 – 46.03 Mb	Chr 11: 104.23 – 104.33 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Tau proteini (ili τ proteini, prema grčkom slovu koje označava ovo ime) su grupa od šest visoko rastvorljivih proteinskih izoformi proizvedenih alternativnom preradom primarnog transkripta gena MAPT (mikrotubulski-asocirani protein tau).^[5][6] Prvenstvenu ulogu imaju u održavanju stabilnosti mikrotubula u aksonima i obiluju neuronima centralnog nervnog sistema (CNS). Manje su česti drugdje, ali se također eksprimiraju na vrlo niskim nivoima u CNS-ovim astrocitima i oligodendrocitima .^[7]

Povezani sa tau proteinima koji su odgovorni za patološka stanje i demencija nervnog sistema, kao što su Alzheimerova i Parkinsonova bolest^[8] Tau proteini postali su hiperfosforilirani nerastvorljivi agregati zvani neurofibrilskii sklopovi. Proteini tau identificirani su 1975. godine, kao termički stabilni proteini, neophodni za sastavljanje mikrotubula^[9][10] > i od tada su okarakterizirani kao suštinski poremećeni proteini.^[11]

Neuroni koji su rasli u kulturi tkiva i obojeni antitelijom na protein MAP2 (zeleno) i MAP tau (crveno) tehnikom imunofluorescencije.
MAP2 se nalazi samo u dendritima i perijedarno, dok se tau nalazi ne samo tu, već i u aksonima.
Kao rezultat, aksoni izgledaju crveno, dok se dendriti i perikarioni čine žutima, zbog preklapanja crvenog i zelenog signala.
DNK je prikazana plavo, pomoću boje DAPI, koja naglašava jedra. Slika ljubaznošću EnCor Biotechnology Inc

Funkcija

Stabilizacija mikrotubula

Kod ljudi, tau proteini se češće nalaze u neuronima nego u neneuronskim ćelijama. Jedna od glavnih funkcija tau-a je moduliranje stabilnosti aksonskih mikrotubula.^[10][12] Ostali sustemski proteini povezani sa mikrotubulama (MAP) mogu obavljati slične funkcije, kao što je predloženu u eksperimentu sa tau nokaut-miševima, koji nisu pokazali abnormalnosti u razvoju mozga – moguće zbog kompenzacije nedostatka tau od strane drugih MAP-ova.^[13][14][15]

Iako je tau prisutan u dendritima na niskim nivoima, gdje je uključen u postsinapsne skele,^[16] aktivan je prvenstveno u distalnim dijelovima aksona, gdje pruža stabilizaciju mikrotubula, ali i fleksibilnost po potrebi. Tau proteini komuniciraju s tubulinom, kako bi stabilizirali mikrotubule i u njima promovirali skupljanje tubulina.^[10] Tau ima dva načina za kontrolu stabilnosti mikrotubula: izoforme i fosforilacija.

Pored funkcije u stabilizaciji mikrotubula, utvrđeno je da Tau regrutuje signalne proteine i regulira aksonski transport posredovan mikrotubulama.^[17]

Translacija proteina

Tau je negativni regulator translacije proteina i u Drosophila ^[12] i moždanoj gangliji kod ljudi.^[18] Njegovo vezanje za ribosome, rezultira oštećenjem ribosomske funkcije, smanjenjem sinteza proteina i promijenjenom u funkciji funkciji sinapsi.^[12][18] Tau specifično komunicira s nekoliko ribosomskih proteina, uključujući presudni regulator translacije rpS6.^[19]

Ponašanje

Primarna nećelijska funkcija tau-a je negativna reguliranje dugoročnog pamćenja^[12] i olakšavanje navikavanja (oblik neasocijativnog učenja),^[12] dvije više i integrirane fiziološke funkcije. Budući da je regulacija tau-a presudna za pamćenje, ovo bi moglo objasniti vezu između tauopatija i kognitivnih oštećenja.

Kod miševa, dok su prijavljeni sojevi nokaut-sojevi bez otvorenog fenotipa u mladosti,^[13][20][21] kad ostare, pokazuju određenu mišićnu slabost, hiperaktivnost i oštećenje uslovljavanja straha.^[22] Međutim, ni prostorno učenje kod miševa,^[22][23][24] ni na kratkotrajnu memoriju (učenje) u Drosophila^[12] izgleda da ne utiče odsustvo tau-a.

Pored toga, tau nokaut-miševi imaju abnormalan ciklus spavanja i budnosti, s povećanim periodima budnosti i smanjenim nebrzih pokreta oka (NREM) tokom spavanja.^[25]

Ostale funkcije

Ostale tipske funkcije tau uključuju ćelijsku signalizaciju, razvoj neurona, neurozaštitu i apoptozu.^[14] Netipske, nestandardne uloge taua ^[26] su također pod aktuelnim istraživanjem, kao što je njihovo sudjelovanje u stabilnosti hromosoma, interakcija sa ćelijskim transkriptomom, interakcije s drugim citoskeletnim ili sinapsnim proteinima, uključenost u mijelinizaciju ili signalizacija u mozak za insulin, njegova uloga u izloženosti hroničnom stresu i depresiji, itd.

Genetika

U ljudi, MAPT gen za kodiranje tau proteina nalazi se na hromosomu 17, pozicija q21, koji sadrži 16 egzona.^[27] Glavni tau protein u ljudskom mozgu je kodiran iz 11 egzona. Egzoni 2, 3 i 10 su alternativno prerađeni u šest tau izoformi.^[28] U ljudskom mozgu, tau proteini čine porodicu od šest izoformi s rasponom od 352–441 aminokiselina. Tau izoforme su različite u nuli, jednom ili dva inserta od 29 aminokiselina na N-terminalnom dijelu (egzoni 2 i 3) i tri ili četiri regije ponavljanja na C-terminalnom dijelu (egzon 10). Dakle, najduža izoforma u CNS-u ima četiri ponavljanja (R1, R2, R3 i R4) i dva inserta (ukupno 441 aminokiselina), dok najkraća izoforma ima tri ponavljanja (R1, R3 i R4) i bez insercija (ukupno 352 aminokiseline).

Gen MAPT ima dvije haplogrupe, H1 i H2, u kojima se gen pojavljuje u obrnutim orijentacijama. Haplogrupa H2 česta je samo u Evropi i kod ljudi koji imaju evropsko porijeklo. Čini se da je haplogrupa H1 povezana s povećanom vjerovatnoćom određenih demencija, poput Alzheimerove bolesti. Prisustvo obje haplogrupe u Europi znači da rekombinacija između obrnutih haplotipova može rezultirati nedostatkom jedne od funkcionalnih kopija gena, što rezultira urođenim defektima.^{[29][30][31][32]}

Struktura

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 758 aminokiselina, a molekulska težina 78.928 Da.^[33].

10		20		30		40		50
MAEPRQEFEV		MEDHAGTYGL		GDRKDQGGYT		MHQDQEGDTD		AGLKESPLQT
PTEDGSEEPG		SETSDAKSTP		TAEDVTAPLV		DEGAPGKQAA		AQPHTEIPEG
TTAEEAGIGD		TPSLEDEAAG		HVTQEPESGK		VVQEGFLREP		GPPGLSHQLM
SGMPGAPLLP		EGPREATRQP		SGTGPEDTEG		GRHAPELLKH		QLLGDLHQEG
PPLKGAGGKE		RPGSKEEVDE		DRDVDESSPQ		DSPPSKASPA		QDGRPPQTAA
REATSIPGFP		AEGAIPLPVD		FLSKVSTEIP		ASEPDGPSVG		RAKGQDAPLE
FTFHVEITPN		VQKEQAHSEE		HLGRAAFPGA		PGEGPEARGP		SLGEDTKEAD
LPEPSEKQPA		AAPRGKPVSR		VPQLKARMVS		KSKDGTGSDD		KKAKTSTRSS
AKTLKNRPCL		SPKHPTPGSS		DPLIQPSSPA		VCPEPPSSPK		YVSSVTSRTG
SSGAKEMKLK		GADGKTKIAT		PRGAAPPGQK		GQANATRIPA		KTPPAPKTPP
SSGEPPKSGD		RSGYSSPGSP		GTPGSRSRTP		SLPTPPTREP		KKVAVVRTPP
KSPSSAKSRL		QTAPVPMPDL		KNVKSKIGST		ENLKHQPGGG		KVQIINKKLD
LSNVQSKCGS		KDNIKHVPGG		GSVQIVYKPV		DLSKVTSKCG		SLGNIHHKPG
GGQVEVKSEK		LDFKDRVQSK		IGSLDNITHV		PGGGNKKIET		HKLTFRENAK
AKTDHGAEIV		YKSPVVSGDT		SPRHLSNVSS		TGSIDMVDSP		QLATLADEVS
ASLAKQGL

Simboli

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

Umoždanom tkivu čovjeka ima šest tau izoformi i razlikuju se po broju veznih domena. Tri izoforme imaju po tri domena vezanja, a ostale tri po četiri. Vezujući domeni nalaze se na karboksi-kraju proteina i pozitivno su nabijeni (omogućavajući mu da se veže za negativno nabijenu mikrotubulu). Izoforme sa četiri vezujuća domena bolje stabilizuju mikrotubule od onih sa tri vezivna domena. Tau je fosfoprotein sa 79 potencijalnih mjesta fosforilacije serina (Ser) i treonina (Thr) na najdužoj tau izoformi. Fosforilacija u normalnim tau proteinima zabilježena je na približno 30 od ovih mjesta.^[34]

Fosforilaciju tau-a regulira mnoštvo kinaza, uključujući PKN, serin/treonin kinazu. Kada se PKN aktivira, fosforilira tau, što rezultira poremećajem organizacije mikrotubula.^[35] Fosforilacija tau-a je također i razvojno regulirana. Naprimjer, fetusni tau je jače fosforiliran u embrionskom CNS-u kod odraslih.^[36] Stepen fosforilacije u svih šest izoformi opada sa godinama usljed aktiviranja fosfataza.^[37] Poput kinaza, i fosfataze imaju ulogu u regulaciji fosforilacije tau-a. Naprimjer, PP2A i PP2B su prisutni u moždanom tkivu čovjeka i imaju sposobnost defosforilacije Ser396.^[38] Vezivanje ovih fosfataza za tau utiče na povezanost tau s mikrotubulama.

Predloženo je i da se fosforilacija tau-a regulira modifikacijom O - GlcNAc na različitim ostacima Ser i Thr.^[39]

Mehanizam

Akumulacija hiperfosforiliranog tau-a u neuronima povezana je sa neurofibrilnom degeneracijom.^[40] Stvarni mehanizam širenja tau iz jedne ćelije u drugu nije dobro identificiran. Također, ostali mehanizmi, uključujući oslobađanje tau-a i toksičnost, nisu jasni. Kao tau agregati, zamjenjuje tubulin, što zauzvrat pojačava fibrilizaciju tau-a.^[41] Predloženo je nekoliko metoda popagacije koje se javljaju sinapsnim kontaktom, kao što su proteini adhezije sinapanih ćelija, neuronska aktivnost i drugi sinapsnii i nesinapsni mehanizmi.^[42] Mehanizam tau agregacije još uvijek nije u potpunosti razjašnjen, ali nekoliko faktora favorizira ovaj proces, uključujući fosforilaciju tau-a i ione cinka.^[43][44]

Otpuštanje

Tau uključuje proces usvajanja i ispuštanja, koji je poznat kao sjetva. Za unos mehanizma tau proteina potrebno je prisustvo heparan-sulfat proteoglikana na ćelijskoj površini, gdje se događa makropinocitoza.^[45] S druge strane, oslobađanje tau-a ovisi o neuronskoj aktivnosti. Mnogi faktori utiču na oslobađanje tau, naprimjer, tip izoformi ili mutacije MAPT-a koje mijenjaju vanćelijski nivo tau-a.^[46] Prema Asaiju i njegovim kolegama, širenje tau proteina događa se iz entorinskog korteksa u hipokampusnu regiju, u ranim fazama bolesti. Također su sugerirali da je mikroglija također bila uključena u proces transporta, a njihova stvarna uloga još uvijek nije poznata.^[47]

Toksičnost

Toksične efekte, tau uzrokuje akumuliranjem unutar ćelija. U mehanizam toksičnosti uključeni su mnogi enzimi, kao što je PAR-1 kinaza. Ovaj enzim stimulira fosforilaciju serina 262 i 356, što zauzvrat dovodi do aktiviranja drugih kinaza (GSK-3 i CDK5), koje uzrokuju fosfoentropiju, povezanu sa bolešću.^[48] Na stupanj toksičnosti utiču različiti faktori, poput stupnja vezanja mikrotubula.^[49][50] Toksičnost bi se mogla dogoditi i neurofibrilarni splet s (NFT), što dovodi do ćelijske smrti i kognitivnog pada.

Klinički značaj

Hiperfosforilacija tau proteina (tau inkluzije, pTau) može rezultirati samosastavljanjem sklopa uparenih spiralnih i ravnih niti, koje su uključene u patogenezu Alzheimerove bolesti, čeonosljepoočne demencije i druge tauopatije.^[51] Svih šest tau izoforami prisutno je u često hiperfosforiliranom stanju u uparenim spiralnim nitima u mozgu osoba sa Alzheimerovom bolesti. U ostalim neurodegenerativnim bolestima zabilježeno je taloženje agregata obogaćenih određenim tau izoformama. Kada se pogrešno sklopi, ovaj inače vrlo rastvorljivi protein, može stvoriti izuzetno nerastvorljive agregate koji doprinose brojnim neurodegenerativnim bolestima. Tau protein ima direktan učinak na razgradnju živih ćelija uzrokovanu sklopovima koje formiraju i blokiraju sinapse živaca.^[52]

Rodno specifična ekspresija gena tau u različitim regijama ljudskog mozga nedavno je uključena u rodne razlike u manifestacijama i riziku od tauopatija.^[53] Neki aspekti funkcionisanja bolesti takođe ukazuju na to da ima neke sličnosti sa prionskim proteinima.^[54]

Interakcije

Dokazano je da protein tau komunicira sa:

• Alfa-sinuklein,^[55][56]
• FYN,^[57]
• Proto-onkogen tirozin-protein kinaza Src
• S100B,^[58][59] i
• YWHAZ.^[60]

Također pogledajte

• Tauopatija
• Dementia pugilistica
• Alzheimerova bolest
• Primarna dobno vezana tauopatija
• Tau astrogliopatija povezana sa starenjem
• Kortikobazna degeneracija
• Progresivna suprajedarna paraliza
• Proteopatija
• Pickova bolest
• Čeonosljepoočna demencija i parkinsonizam povezani s hromosomom 17
• Prion

Reference

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Vanjski linkovi

• tau Proteins na US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders
• MR scans of variant CJD CSF tau-positive man
• P10636