HTT

Huntingtin (Htt) jest protein koji je kod ljudi kodiran genom HTT sa hromosoma 4. Gn je poznat i kao IT15 ("'interesni transkript 15'").^[5] Mutirani HTT je uzrok Huntingtonove bolesti (HD), a eksprimirana je zbog ove uloge i uključenosti u dugotrajno skladištenje memorije.^[6]

HTT
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 3IO6, 3IOU, 3LRH, 4FE8, 4FEB, 4FEC, 4FED, 2LD0, 2LD2, 3IO4, 3IOR, 3IOT, 3IOV, 3IOW, 4RAV
Identifikatori
Aliasi	HTT
Vanjski ID-jevi	OMIM: 613004 MGI: 96067 HomoloGene: 1593 GeneCards: HTT
Lokacija gena (čovjek) Hrom. Hromosom 4 (čovjek)[1] Bend 4p16.3 Početak 3,041,363 bp[1] Kraj 3,243,957 bp[1]
Lokacija gena (miš) Hrom. Hromosom 5 (miš)[2] Bend 5 B2|5 17.92 cM Početak 34,919,084 bp[2] Kraj 35,069,878 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • profilin binding • dynactin binding • transmembrane transporter binding • p53 binding • transcription factor binding • GO:0001948, GO:0016582 vezivanje za proteine • beta-tubulin binding • vezivanje identičnih proteina • dynein intermediate chain binding • kinase binding • heat shock protein binding Ćelijska komponenta • late endosome • Golđijev aparat • nukleoplazma • Autofagosom • Endoplazmatski retikulum • Centriole • cytoplasmic vesicle membrane • dendrit • citosol • Akson • jedro • citoplazma • inclusion body • perinuklearno područje citoplazme • GO:0009327 makromolekulani kompleks • presynaptic cytosol • postsynaptic cytosol Biološki proces • animal organ development • retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum • Golgi organization • vesicle transport along microtubule • negative regulation of extrinsic apoptotic signaling pathway • establishment of mitotic spindle orientation • positive regulation of cilium assembly • positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity • GO:0097285 apoptoza • vocal learning • positive regulation of lipophagy • positive regulation of autophagy of mitochondrion • positive regulation of aggrephagy • regulation of phosphoprotein phosphatase activity • protein destabilization • positive regulation of apoptotic process • regulation of CAMKK-AMPK signaling cascade • regulation of cAMP-dependent protein kinase activity Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	3064	15194
Ensembl	ENSG00000197386	ENSMUSG00000029104
UniProt	P42858	P42859
RefSeq (mRNK)	NM_002111 NM_001388492	NM_010414
RefSeq (bjelančevina)	NP_002102	NP_034544
Lokacija (UCSC)	Chr 4: 3.04 – 3.24 Mb	Chr 5: 34.92 – 35.07 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 3.142 aminokiseline, а molekulska težina 347.603 Da.^[7]

• 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
MATLEKLMKA		FESLKSFQQQ		QQQQQQQQQQ		QQQQQQQQPP		PPPPPPPPPQ
LPQPPPQAQP		LLPQPQPPPP		PPPPPPGPAV		AEEPLHRPKK		ELSATKKDRV
NHCLTICENI		VAQSVRNSPE		FQKLLGIAME		LFLLCSDDAE		SDVRMVADEC
LNKVIKALMD		SNLPRLQLEL		YKEIKKNGAP		RSLRAALWRF		AELAHLVRPQ
KCRPYLVNLL		PCLTRTSKRP		EESVQETLAA		AVPKIMASFG		NFANDNEIKV
LLKAFIANLK		SSSPTIRRTA		AGSAVSICQH		SRRTQYFYSW		LLNVLLGLLV
PVEDEHSTLL		ILGVLLTLRY		LVPLLQQQVK		DTSLKGSFGV		TRKEMEVSPS
AEQLVQVYEL		TLHHTQHQDH		NVVTGALELL		QQLFRTPPPE		LLQTLTAVGG
IGQLTAAKEE		SGGRSRSGSI		VELIAGGGSS		CSPVLSRKQK		GKVLLGEEEA
LEDDSESRSD		VSSSALTASV		KDEISGELAA		SSGVSTPGSA		GHDIITEQPR
SQHTLQADSV		DLASCDLTSS		ATDGDEEDIL		SHSSSQVSAV		PSDPAMDLND
GTQASSPISD		SSQTTTEGPD		SAVTPSDSSE		IVLDGTDNQY		LGLQIGQPQD
EDEEATGILP		DEASEAFRNS		SMALQQAHLL		KNMSHCRQPS		DSSVDKFVLR
DEATEPGDQE		NKPCRIKGDI		GQSTDDDSAP		LVHCVRLLSA		SFLLTGGKNV
LVPDRDVRVS		VKALALSCVG		AAVALHPESF		FSKLYKVPLD		TTEYPEEQYV
SDILNYIDHG		DPQVRGATAI		LCGTLICSIL		SRSRFHVGDW		MGTIRTLTGN
TFSLADCIPL		LRKTLKDESS		VTCKLACTAV		RNCVMSLCSS		SYSELGLQLI
IDVLTLRNSS		YWLVRTELLE		TLAEIDFRLV		SFLEAKAENL		HRGAHHYTGL
LKLQERVLNN		VVIHLLGDED		PRVRHVAAAS		LIRLVPKLFY		KCDQGQADPV
VAVARDQSSV		YLKLLMHETQ		PPSHFSVSTI		TRIYRGYNLL		PSITDVTMEN
NLSRVIAAVS		HELITSTTRA		LTFGCCEALC		LLSTAFPVCI		WSLGWHCGVP
PLSASDESRK		SCTVGMATMI		LTLLSSAWFP		LDLSAHQDAL		ILAGNLLAAS
APKSLRSSWA		SEEEANPAAT		KQEEVWPALG		DRALVPMVEQ		LFSHLLKVIN
ICAHVLDDVA		PGPAIKAALP		SLTNPPSLSP		IRRKGKEKEP		GEQASVPLSP
KKGSEASAAS		RQSDTSGPVT		TSKSSSLGSF		YHLPSYLKLH		DVLKATHANY
KVTLDLQNST		EKFGGFLRSA		LDVLSQILEL		ATLQDIGKCV		EEILGYLKSC
FSREPMMATV		CVQQLLKTLF		GTNLASQFDG		LSSNPSKSQG		RAQRLGSSSV
RPGLYHYCFM		APYTHFTQAL		ADASLRNMVQ		AEQENDTSGW		FDVLQKVSTQ
LKTNLTSVTK		NRADKNAIHN		HIRLFEPLVI		KALKQYTTTT		CVQLQKQVLD
LLAQLVQLRV		NYCLLDSDQV		FIGFVLKQFE		YIEVGQFRES		EAIIPNIFFF
LVLLSYERYH		SKQIIGIPKI		IQLCDGIMAS		GRKAVTHAIP		ALQPIVHDLF
VLRGTNKADA		GKELETQKEV		VVSMLLRLIQ		YHQVLEMFIL		VLQQCHKENE
DKWKRLSRQI		ADIILPMLAK		QQMHIDSHEA		LGVLNTLFEI		LAPSSLRPVD
MLLRSMFVTP		NTMASVSTVQ		LWISGILAIL		RVLISQSTED		IVLSRIQELS
FSPYLISCTV		INRLRDGDST		STLEEHSEGK		QIKNLPEETF		SRFLLQLVGI
LLEDIVTKQL		KVEMSEQQHT		FYCQELGTLL		MCLIHIFKSG		MFRRITAAAT
RLFRSDGCGG		SFYTLDSLNL		RARSMITTHP		ALVLLWCQIL		LLVNHTDYRW
WAEVQQTPKR		HSLSSTKLLS		PQMSGEEEDS		DLAAKLGMCN		REIVRRGALI
LFCDYVCQNL		HDSEHLTWLI		VNHIQDLISL		SHEPPVQDFI		SAVHRNSAAS
GLFIQAIQSR		CENLSTPTML		KKTLQCLEGI		HLSQSGAVLT		LYVDRLLCTP
FRVLARMVDI		LACRRVEMLL		AANLQSSMAQ		LPMEELNRIQ		EYLQSSGLAQ
RHQRLYSLLD		RFRLSTMQDS		LSPSPPVSSH		PLDGDGHVSL		ETVSPDKDWY
VHLVKSQCWT		RSDSALLEGA		ELVNRIPAED		MNAFMMNSEF		NLSLLAPCLS
LGMSEISGGQ		KSALFEAARE		VTLARVSGTV		QQLPAVHHVF		QPELPAEPAA
YWSKLNDLFG		DAALYQSLPT		LARALAQYLV		VVSKLPSHLH		LPPEKEKDIV
KFVVATLEAL		SWHLIHEQIP		LSLDLQAGLD		CCCLALQLPG		LWSVVSSTEF
VTHACSLIYC		VHFILEAVAV		QPGEQLLSPE		RRTNTPKAIS		EEEEEVDPNT
QNPKYITAAC		EMVAEMVESL		QSVLALGHKR		NSGVPAFLTP		LLRNIIISLA
RLPLVNSYTR		VPPLVWKLGW		SPKPGGDFGT		AFPEIPVEFL		QEKEVFKEFI
YRINTLGWTS		RTQFEETWAT		LLGVLVTQPL		VMEQEESPPE		EDTERTQINV
LAVQAITSLV		LSAMTVPVAG		NPAVSCLEQQ		PRNKPLKALD		TRFGRKLSII
RGIVEQEIQA		MVSKRENIAT		HHLYQAWDPV		PSLSPATTGA		LISHEKLLLQ
INPERELGSM		SYKLGQVSIH		SVWLGNSITP		LREEEWDEEE		EEEADAPAPS
SPPTSPVNSR		KHRAGVDIHS		CSQFLLELYS		RWILPSSSAR		RTPAILISEV
VRSLLVVSDL		FTERNQFELM		YVTLTELRRV		HPSEDEILAQ		YLVPATCKAA
AVLGMDKAVA		EPVSRLLEST		LRSSHLPSRV		GALHGVLYVL		ECDLLDDTAK
QLIPVISDYL		LSNLKGIAHC		VNIHSQQHVL		VMCATAFYLI		ENYPLDVGPE
FSASIIQMCG		VMLSGSEEST		PSIIYHCALR		GLERLLLSEQ		LSRLDAESLV
KLSVDRVNVH		SPHRAMAALG		LMLTCMYTGK		EKVSPGRTSD		PNPAAPDSES
VIVAMERVSV		LFDRIRKGFP		CEARVVARIL		PQFLDDFFPP		QDIMNKVIGE
FLSNQQPYPQ		FMATVVYKVF		QTLHSTGQSS		MVRDWVMLSL		SNFTQRAPVA
MATWSLSCFF		VSASTSPWVA		AILPHVISRM		GKLEQVDVNL		FCLVATDFYR
HQIEEELDRR		AFQSVLEVVA		APGSPYHRLL		TCLRNVHKVT		TC

Pregled

Promjenjiv je u svojoj strukturi, jer mnogi polimorfizmi gena mogu dovesti do promjenjivog broja glutaminskih ostataka u proteinu. U svom divljem tipu (normalnom obliku), sadrži 6-35 ostataka glutamina. Međutim, kod osoba pogođenih Huntingtonovom bolešću (autosomno dominantni genetički poremećaj), sadrži više od 36 glutaminskih ostataka (najveća prijavljena dužina ponavljanja je oko 250).^[8] Njegovo uobičajeno ime je izvedeno od ove bolesti; ranije se običnono koristila oznaka IT15.

Masa huntingtinskog proteina u velikoj meri zavisi od broja glutaminskih ostataka koje ima; predviđena masa je oko 350 kDa. Općenito je prihvaćeno da normalni huntingtin ima 3144 aminokiseline. Tačna funkcija ovog proteina nije poznata, ali on igra važnu ulogu u nervnim ćelijama. Unutar ćelija, huntingtin može, ali i ne mora biti uključen u signalizaciju, transport materijala, vezivanje proteina i drugih struktura, i zaštitu od apoptoza oblika programirane ćelijske smrti. Huntingtinski protein je potreban za normalan razvoj prije rođenja.^[9] Izražava se u mnogim tkivima u tijelu, s najvišim nivoima ekspresije u mozgu.

Gen

Usmjernost 5′-kraj (pet primarnih krajeva) "HTT" gena ima sekvencu od tri DNK baze, citozin-adenin-]]guanin (CAG), za kodiranje aminokiseline glutamin, što se ponavlja više puta. Ova regija se naziva trinukleotidno ponavljanje. Uobičajeni broj ponavljanja CAG je između sedam i 35 puta.

HTT gen nalazi se na kratkom kraku (p) hromosoma 4, na poziciji 16.3, od baznog para 3,074.510 do baznog para 3,243.960.^[10]

Protein

Funkcija

Funkcija huntingtina (Htt) nije dobro shvaćena, ali je uključena u aksonski transport.^[11] Huntingtin je neophodan za razvoj, a njegovo odsustvo je smrtonosno za miševe.^[9] Protein nema homologiju sekvence sa drugim proteinima i visoko je eksprimiran u neuronima i testisima kod ljudi i glodara.^[12] Huntingtin pojačava regulaciju ekspresije moždanog neutrotrofnog faktora (BDNF) na nivou transkripcije, ali mehanizam kojim huntingtin reguliše ekspresiju gena nije određen.^[13] Iz imunohistohemijske, elektronske mikroskopije i subćelijske frakcionacije studija molekula, otkriveno je da je huntingtin prvenstveno povezan sa [ vezikulama i mikrotubulama.^[14][15] Ukazuju na funkcionalnu ulogu u citoskeletnom sidrenju ili transportu mitohondrija. Htt protein je uključen u promet vezikula jer je u interakciji sa HIP1, proteinom koji vezuje klatrin, da posreduje endocitozu, promet materijala u ćeliju.^[16][17] Takođe se pokazalo da huntingtin ima ulogu u uspostavljanju polarnosti epitela preko interakcije sa RAB11A.^[18]

Interakcije

Utvrđeno je da huntingtin direktno stupa u interakciju s najmanje 19 drugih protein a, od kojih se šest koristi za transkripciju, četiri za transport, tri za ćelijdku signalizaciju i šest ostalih je nepoznate funkcije (HIP5, HIP11, HIP13, HIP15, HIP16 i CGI-125).^[19] Pronađeno je preko 100 interakcijskih proteina, kao što su huntington-vezani protein 1 (HAP1) i huntingtin interaktivni protein 1 (HIP1), obično pronađeni korištenjem dvohibridnog skrininga i potvrđeni imunoprecipitacijom.^[20][21]

Interaktivni protein	Ovisnost o dužini PolyQ	Funkcija
α-Adaptin C/HYPJ	Da	Endocitoza
Akt/PKB	Ne	Kinaza
CBP	Da	Transkripcijski koaktivator sa acetultransferaznom aktivnošću
CA150	Ne	Transkripcijski aktivator
CIP4	Da	cdc42-ovisna transdukcija signala
CtBP	Da	Transkripcijski faktor
FIP2	Nepoznato	Ćelijska morfogeneza
Grb2[22]	Nepoznato	Vezujući protein receptora faktora rasta
HAP1	Da	Membranski promet
HAP40 (F8A1, F8A2, F8A3)	Nepoznato	Nepoznata
HIP1	Da	Proapotozna endocitoza
HIP14/HYP-H	Da	Promet, endocitoza
N-CoR	Da	Korepresor jedarnog receptora
NF-κB	Nepoznato	Transkripcijski faktor
p53[23]	Ne	Transkripcijski faktor
PACSIN1[24]	Da	Endocitoza, citoskeletni aktin
DLG4 (PSD-95)	Da	Postsinapsna gustoća 95
RASA1 (RasGAP)[22]	Nepoznato	Protein aktivacije Ras GTPaze
SH3GL3[25]	Da	Endocitoza
SIN3A	Da	Transkripcijski represor
Sp1[26]	DA	Transkripcijski faktor

Također je pokazano da je huntingtin u interakciji sa:

• HIP2,^[27]
• MAP3K10,^[28]
• OPTN,^[29]
• PRPF40A,^[30]
• SETD2,^[30]
• TRIP10,^[31] i
• ZDHHC17.^[30][32]

Mitohondrijska disfunkcija

Mutant huntingtin (mHtt) ima ključnu ulogu u mitohondrijalnoj disfunkciji, uključujući inhibiciju mitohondrijski transport elektrona, viši nivo reaktivnih vrsta kisika i povećan oksidativni stres.^[33] Mutantni protein huntingtin također podstiče oksidativno oštećenje DNK koje može doprinijeti patološkim promjenama u Huntingtonovoj bolesti.^[34]

Klinički značaj

Glavni članak: Huntingtonova bolest

Klasifikacija trinukleotidnog ponavljanja i rezultirajućeg statusa bolesti zavisno od broja CAG ponavljanja ^[35]

Broj ponavljanja	Klasifikacija	Status bolesti
<26	Normalan	Nepogođeni
27–35	Umjerana	Nepogođeni
36–40	Smanjena penetracija	+/– Pogođeni
>40	Potpuna penetracija	Pogođeni

Huntingtonova bolest (HD) je uzrokovana mutiranim oblikom gena huntingtin, gdje prekomjerno (više od 36) CAG ponavljanja rezultira stvaranjem nestabilnog proteina.^[35] Ova proširena ponavljanja dovode do proizvodnje proteina huntingtin koji sadrži abnormalno dug poliglutaminski trakt na N-terminalu. To ga čini dijelom klase neurodegenerativnih poremećaja poznatih kao poremećaji trinukleotidnih ponavljanja ili poliglutaminski poremećaji. Ključna sekvenca koja se nalazi kod Huntingtonove bolesti je ponovljena ekspanzija trinukleotida ostataka glutamina koji počinju od 18. aminokiseline. Kod nepogođenih osoba, sadrži između devet i 35 glutaminskih ostataka bez štetnih efekata.^[5] Međutim, 36 ili više ostataka stvaraju pogrešan mutantni oblik Htt, (mHtt). Smanjena penetrsbilnodt nalazi se u tačkama 36–39.^[36]

Enzimi u ćeliji često sjeku ovaj izduženi protein na fragmente. Fragmenti proteina formiraju abnormalne nakupine, poznate kao neuronske unutarjedarne inkluzije (NII), unutar nervnih ćelija, i mogu privući druge, normalne proteine u nakupine. Smatralo se da karakteristično prisustvo ovih nakupina kod pacijenata doprinosi razvoju Huntingtonove bolesti.^[37] Međutim, kasnija istraživanja postavila su pitanja o ulozi inkluzija (grudica), pokazujući da je prisustvo vidljivih NII produžilo život neurona i djelovalo na smanjenje unutarćelijskog mutantnog huntingtina u susjednim neuronima.^[38] Jedan od zbunjujućih faktora je to što se sada prepoznaje da različiti tipovi agregata formiraju mutantni protein, uključujući proteinske naslage koje su premale da bi se prepoznale kao vidljive u gore navedenim studijama.^[39] I dalje je teško predvidjeti vjerovatnoću neuronske smrti. Vjerovatno je važno više faktora, uključujući: (1) dužinu CAG ponavljanja u huntingtinskom genu i (2) izloženost neurona difuznom unutarćelijskom mutantnom proteinu huntingtin. NII (skupljanje proteina) mogu biti od pomoći kao mehanizam za suočavanje – a ne samo kao patogeni mehanizam – za zaustavljanje smrti neurona, smanjenjem količine difuznog huntingtina.^[40] Za ovaj proces je posebno vjerovatno da će se dogoditi prvenstveno u strijatumu (dio mozga koji koordinira kretanje) i čeonom korteksu (dio mozga koji kontrolira razmišljanje i emocije).

Ljudi sa 36 do 40 CAG ponavljanja mogu, ali i ne moraju razviti znakove i simptome Huntingtonove bolesti, dok će oni s više od 40 ponavljanja razviti poremećaj tokom normalnog života. Kada ima više od 60 CAG ponavljanja, osoba razvija teški oblik HD poznat kao juvenilna HD. Stoga broj ponavljanja CAG (sekvencije koja kodira aminokiselinu glutamin) utiče na dob početka bolesti. Nijedan slučaj HD nije dijagnosticiran s brojem manjim od 36.^[36]

Kako se izmijenjeni gen prenosi s jedne generacije na drugu, veličina CAG ponovljene ekspanzije može se promijeniti; često se povećava u veličini, posebno kada je naslijeđen od oca. Nije prijavljeno da ljudi sa 28 do 35 CAG ponavljanja razviju poremećaj, ali njihova djeca su u riziku da obole od bolesti ako se ekspanzija ponavljanja poveća.

Reference

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Vanjski linkovi

• Huntingtin protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
• The Huntingtin Protein and Protein Aggregation at HOPES Arhivirano 27. 8. 2020. na Wayback Machine : Huntington's Outreach Project for Education at Stanford
• The HDA Huntington's Disease Association UK
• OMIM: 143100
• EntrezGene 3064
• GeneCard
• iHOP