TNNT2

TNNT2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1J1D, 1J1E, 4Y99

Identifikatori
AliasiTNNT2
Vanjski ID-jeviOMIM: 191045 MGI: 104597 HomoloGene: 68050 GeneCards: TNNT2
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za TNNT2
Genomska lokacija za TNNT2
Bend1q32.1Početak201,359,008 bp[1]
Kraj201,377,764 bp[1]
Lokacija gena (miš)
Hromosom 1 (miš)
Hrom.Hromosom 1 (miš)[2]
Hromosom 1 (miš)
Genomska lokacija za TNNT2
Genomska lokacija za TNNT2
Bend1 E4|1 59.32 cMPočetak135,764,092 bp[2]
Kraj135,779,998 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• protein-macromolecule adaptor activity
• ATPase activity
• GO:0001948, GO:0016582 vezivanje za proteine
• actin binding
• tropomyosin binding
• troponin C binding
• troponin I binding
• calcium ion binding
• calcium-dependent ATPase activity
Ćelijska komponenta• citosol
• troponin complex
• Sarkomera
• striated muscle thin filament
• Miofibril
• cardiac myofibril
• cardiac Troponin complex
Biološki proces• regulation of muscle contraction
• Mišićna kontrakcija
• regulation of heart contraction
• positive regulation of ATP-dependent activity
• negative regulation of ATP-dependent activity
• response to calcium ion
• ventricular cardiac muscle tissue morphogenesis
• actin crosslink formation
• muscle filament sliding
• regulation of muscle filament sliding speed
• cardiac muscle contraction
• protein heterooligomerization
• skeletal muscle contraction
• sarcomere organization
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

7139

21956

Ensembl

ENSG00000118194

ENSMUSG00000026414

UniProt

P45379

P50752

RefSeq (mRNK)
NM_000364
NM_001001430
NM_001001431
NM_001001432
NM_001276345

NM_001276346
NM_001276347

NM_001130174
NM_001130175
NM_001130176
NM_001130177
NM_001130178

NM_001130179
NM_001130180
NM_001130181
NM_011619

RefSeq (bjelančevina)
NP_000355
NP_001001430
NP_001001431
NP_001001432
NP_001263274

NP_001263275
NP_001263276

NP_001123646
NP_001123647
NP_001123648
NP_001123649
NP_001123650

NP_001123651
NP_001123652
NP_001123653
NP_035749

Lokacija (UCSC)Chr 1: 201.36 – 201.38 MbChr 1: 135.76 – 135.78 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Srčanomišićni troponin T (cTnT) jest protein koji je kod ljudi kodiran genom TNNT2 sa hromosoma 1.[5][6] Srčani TnT je tropomiozin-vezujuća podjedinica troponinskog kompleksa, koja se nalazi na tankom filamentu poprečnoprugastih mišića i reguliše mišićnu kontrakciju kao odgovor na promjene u koncentraciji unutarćelijskih iona kalcija.

U ljudskom hromosomskom genomu, TNNT2 gen nalazi se na pozicijki 1q32, koja kodira izoformu srčanog mišića troponina T (cTnT). Ljudski cTnT je protein od ~36 kDa koji se sastoji od 297 aminokiselina uključujući prvi metionin sa izoelektričnom tačkom (pI) od 4,88. To je tropomiozin-vezujuća i tanka filamentna podjedinica troponinskog kompleksa u ćelijama srčanog mišića.[7][8][9] TNNT2 gen eksprimira se u srčanom mišiću kičmenjaka i skeletnim mišićima embriona.[8][9][10]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 298 aminokiselina, a molekulska težina 35.924 Da.[11]

1020304050
MSDIEEVVEEYEEEEQEEAAVEEEEDWREDEDEQEEAAEEDAEAEAETEE
TRAEEDEEEEEAKEAEDGPMEESKPKPRSFMPNLVPPKIPDGERVDFDDI
HRKRMEKDLNELQALIEAHFENRKKEEEELVSLKDRIERRRAERAEQQRI
RNEREKERQNRLAEERARREEEENRRKAEDEARKKKALSNMMHFGGYIQK
QAQTERKSGKRQTEREKKKKILAERRKVLAIDHLNEDQLREKAKELWQSI
YNLEAEKFDLQEKFKQQKYEINVLRNRINDNQKVSKTRGKAKVTGRWK

Struktura

Srčani TnT je protein od 35,9 kDa koji se sastoji od 298 aminokiselina.[12][13] Najveća je od tri troponinske podjedinice (cTnT, troponin I (TnI), troponin C (TnC)) na aktinskom tankom filamentu srčanog mišića. Struktura TnT je asimetrična; globulski C-terminalni domen je u interakciji sa tropomiozinom (Tm), TnI i TnC, sa N-terminalnim vezom koja snažno vezuje Tm. N-terminalni region TnT je alternativno prerađen, što uzrokuje pojavu više izoformi uočenih u srčanom mišiću.[14]

Funkcija

Kao dio troponinskog kompleksa, funkcija cTnT je da regulira kontrakciju mišića. N-terminalni region TnT koji snažno vezuje aktin najverovatnije se pomjera sa Tm i aktinom tokom jakog miozinskog poprečnog vezivanja i stvaranja sile . Ovaj region je vjerovatno uključen u transdukciju kooperativnosti niz tanki filament.[15] C-terminalni region TnT čini dio domena globulastog troponinskog kompleksa i učestvuje u korištenju osetljivost na kalcij jakog miozinskog poprečnog mosta koji se vezuje za tanki filament.[16]

Alternativna prerada

TNNT2 gen sisara sadrži 14 konstitutivnih egzona i tri alternativno preražena egzona.[17] Egzoni 4 i 5 koji kodiraju N-terminalni varijabilni region i egzon 13 između srednjeg i C-terminalnog regiona su alternativno prerađeni.[18] Egzon 5 kodira segment od 9 ili 10 aminokiselina koji je visoko kiseo i negativno nabijen pri fiziološkom pH.[8] Ekgzon 5 eksprimira se u srcu embriona, a reguliše naniže i prestaje ekspresiju tokom postnatalnog razvoja.[19]

Embrionalni cTnT s više negativnog naboja na N-terminalnom području pokazuje veću osjetljivost na kalcij, aktivnost aktomiozinske ATPaze i proizvodnju sile miofilamenta, u poređenju sa srčanim TnT odraslih osoba, kao i veću toleranciju na acidozu.[20] TNNT2 gen je prolazno eksprimiran u embrionalnim i neonatalnim skeletnim mišićima i kod ptičjih i kod sisara.[21][22][23] Kada se TNNT2 eksprimira u neonatusnog skeletnog mišića, alternativna prerada egzona 5 pokazuje sinhronizovanu regulaciju sa onom u srcu na način specifičan za vrstu.[21] Ovaj fenomen ukazuje da je alternativna perada pre-iRNK TNNT2 pod kontrolom genetički ugrađenog sistemskog biološkog sata.

Posttranslacijske modifikacije

Fosforilacija

Ser2 cTnT na N-terminalu fosforiliran je konstitutivno nepoznatim mehanizmima.[7] Pronađeno je da je cTnT fosforiliran putem PKC na Thr197, Ser201, Thr206, Ser208 i Thr287 u C-terminalnoj regiji. Samo fosforilacija Thr206 bila je dovoljna da smanji osjetljivost miofilamenta na kalcij i proizvodnju sile. cTnT je također fosforiliran na Thr194 i Ser198 u uslovima stresa,[24] što dovodi do oslabljene kontraktilnosti kardiomiocita. Pokazalo se da fosforilacija cTnT na Ser278 i Thr287 pomoću ROCK-II smanjuje aktivnost miozinske ATPaze i razvoj sile miofilamenta u prekrivenom srčanom mišiću.[25] Tabela 1 sumira modifikacije fosforilacije cTnT i moguće funkcije.

O-vezana GlcNAcilacija

cTnT se sve više modificira na Ser190 O-GlcNAcilacijom tokom razvoja srčane insuficijencije kod pacova, praćeno smanjenom fosforilacijom Ser208.[26]

Proteolitska modifikacija

U apoptotskim kardiomiocitima, cTnT je razdvojen kaspazom 3, da bi se stvorio skraćeni fragment od 25 kDa na N-terminalnom dijelu.[27] Ova destruktivna fragmentacija uklanja dio srednjeg područja vezivanja tropomiozina 1,[28] dovodeći do slabljenja proizvodnje sile miofilamenta, smanjenjem aktivnosti miozinske ATPaze.

U srčanom mišiću u uslovima stresa, srčani TnT se cijepa kalpainom I, restriktivno uklanjajući čitavu varijabilnu regiju N-terminala.[29][30] Ova proteolitska modifikacija cTnT se javlja u srčanom mišiću u akutnoj ishemiji-reperfuziji ili preopterećenju pritiskom.[31]

Restriktivno skraćeni cTnT na N-terminalnom dijelu ostaje funkcionalan u miofilamentima i dovodi do smanjene kontraktilne brzine ventrikularnog mišića, što produžava fazu brzog izbacivanja i rezultira povećanjem udarnog volumena, posebno pod povećanim naknadnim opterećenjem.[31] In vitro studije pokazale su da je N-terminalni skraćeni cTnT očuvao ukupnu osjetljivost srčanog miofilamenta na kalcij i kooperativnost, ali je promijenio afinitete vezivanja TnT-a za tropomiozin, TnI i TnC proteine,[32] i dovode do blago smanjene maksimalne aktivnosti miozinske ATPaze i proizvodnje sile miofilamenta, što čini osnovu selektivnog smanjenja kontraktilne brzine srčanokomornog mišića, kako bi se povećao udarni volumen, bez značajnog povećanja potrošnje energije.[31]

Sa relativno kratkim poluživotom cTnT u kardiomiocitima (3-4 dana),[33] N-terminalni skraćeni cTnT bi bio zamijenjen novosintetiziranim netaknutim cTnT za nekoliko dana. Stoga ovaj mehanizam obezbjeđuje reverzibilnu posttranslacionu regulaciju za modulaciju srčane funkcije u prilagođavanju na stresne uslove.

Mesta fosforilacije u cTnT u poređenju sa ssTnT i fsTnT
Mjesto fosforilacije Kinaza Funkcija Reference
cTnT ssTnT fsTnT
Ser2 c c PKC Nepoznata [34][35][36]
Thr197 n N PKC Bez utijaja na funkciju [37][38]
Ser201 n n PKC Bez utijaja na funkciju [37][38]
Thr204 n n PKC Smanjuje aktivnost miozinske ATPaze, proizvodi sile miofilamenta i osjetljivost Ca2+ [38][39][40]
Thr204 n n CaMK II Nepotnata [41]
Thr204 n n ASK I Smanjuje kontraktilnost kardiomiocita [24]
Thr206 PKC Smanjuje Ca2+ osjetljivost, aktivnost aktomiozin ATPaze i razvoj napetosti [37]
Ser208 n n PKC Smanjuje aktivnost miozin ATPaze, mijenja osjetljivost miofilamenta Ca2+ [38][40][42]
Ser208 n n ASK I Smanjuje kontraktilnost kardiomiocita [24]
Thr213 c c PKC Smanjuje aktivnost miozin ATPaze, proizvodnju sile miofilamenta i Ca2+ osjetljivost [43]
Thr213 c c Raf-1 Nepoznata [44]
Ser285 n c PKC Smanjuje aktivnost miozin ATPaze, proizvodnju sile miofilamenta i Ca2+ osjetljivost [42]
Ser285 n c ROCK-II Smanjuja razvoj sile miofilamenta, aktivnost miozin ATPaze i Ca2+ osjetljivost [25]
Thr294 n n PKC Smanjuje aktivnost miozin ATPaze, proizvodnju sile miofilamenta i Ca2+ osjetljivost [38][39][40][42]
Thr294 n n ROCK-II Smanjuje razvoj sile miofilamenta, aktivnost miozin ATPaze i osjetljivost na Ca2+ [25]

Sumirani su rezidui u srčanom TnT sa regulacijom fosforilacije. Broj ostataka za fosforilacijski serin i treonin je onaj u ljudskom srčanom TnT sa uključenim prvim metioninom. Fosforilacija srčanog TnT na ovim ostacima upoređena je sa parnjacima u brzom TnT i sporom TnT. C, konzerciran; N je nekonzerviran. Također navedene su i kinaze odgovorne za svaku fosforilaciju, funkcionalne efekte.

Mutacije u kardiomiopatijama

Tačkaste mutacije u genu TNNT2 uzrokuju različite tipove kardiomiopatija, uključujući hipertrofnu kardiomiopatiju (HCM), proširenu kardiomiopatiju (DCM) i restriktivnu kardiomiopatiju (RCM). Tabela u nastavku rezimira reprezentativne TNNT2 mutacije i abnormalne spojeve pronađene kod ljudskih i životinjskih kardiomiopatija.

Reprezentativne TNNT2 mutacije i abnormalne prerade koje uzrokuju kardiomiopatiju
Mutacija Dijagnoza Referenca
Ile79Asn HCM [45][46][47]
Arg92Gln HCM [45][48]
Intron 16G1→A (D14 and D28+7) HCM [45]
Arg92Leu HCM [47][49]
Arg92Trp HCM [50][51][52]
Arg94Leu HCM [47][53]
Arg94Cys HCM [54]
ΔE96 RCM [55][56]
Ala104Val HCM [57]
Phe110Ile DCM [58][59]
Arg130Cys HCM [60]
Arg131Trp DCM [61][62]
E136K RCM [63]
Arg141Trp DCM [64][65]
DGlu160 HCM [66]
Glu163Arg HCM [60]
Glu163Lys HCM [58]
Ser179Phe HCM [67]
Arg205Leu DCM [61]
DLys210 DCM [68][69][70]
Glu244Asp HCM [58]
Asp270Asn DCM [68]
Lys273Glu DCM [71]
Arg278Cys HCM [58][72]

Aminokiselinski ostaci mutacija su numerisani kao u ljudskom srčanom TnT, sa uključenim prvim metioninom. Mutacije srčanog TnT koje su uzrokovale kardiomiopatije uglavnom su nađene u komnzerviranim srednjim i C-terminalnim regijama.

Klinički značaj

Mutacije ovog gena povezane su sa porodičnom hipertrofnom kardiomiopatijom, kao i sa restriktivnom[73] i dilatacijskom kardiomiopatijom. Transkripti za ovaj gen prolaze kroz alterasnivnu preradu, što rezultira mnogim tkivno specifičnim izoformama; međutim, priroda pune dužine nekih od ovih varijanti još nije utvrđena. Mutacije ovog gena mogu biti povezane sa blagom ili odsutnom hipertrofijom i dominantnom restriktivnom bolešću, sa visokim rizikom od iznenadne srčane smrti.[73] Može doći do bržeg napredovanja dilatacijske kardiomiopatije kod pacijenata sa TNNT2 mutacijama, nego kod onih sa mutacijama teškog lanca miozina.[50][71]

Evolucija

Par grna TnT i TnI

Kod kičmenjaka, evoluirala su tri homologna gena, koji kodiraju tri izoforme TnT specifične za tip mišića.[9] Svaki od gena izoformi TnT vezan je u hromosomskoj DNK sa genom izoforme troponina I (TnI), koji kodira inhibitornu podjedinicu troponinskog kompleksa i formira tri para gena: brzi skeletni mišić TnI (fsTnI)-fsTnT, spori skeletni mišić TnI ( ssTnI)-cTnT i cTnI-ssTnT parovi. Studije o konzerviranosti sekvenci i epitopa sugeriraju da geni koji kodiraju izoforme TnT i TnI specifične za tip mišića potiču iz predačkog gena sličnog TnI i dupliciraju se i diverzificiraju iz para gena sličnog fsTnI-u i fsTnT.[28]

Filogenetsko stablo gena TNNT2

Očigledno isprepletena veza između ssTnI-cTnT i cTnI-ssTnT gena zapravo odražava originalne funkcionalne veze jer je gen TNNT2 eksprimiran zajedno sa ssTnI genom u embrionskom srčanom mišiću.[21] Poravnavanje proteinske sekvence gena pokazalo je da je TNNT2 gen pkouzzerviran kod vrsta kičmenjaka (slika 2) u srednjem i C-terminalnom području, dok se tri izoforme mišićnog tipa značajno razlikuju.[8][9]

Klinički značaj

Mutacije ovog gena povezane su sa porodičnom hipertrofnom kardiomiopatijom, kao i sa restriktivnom[73] i dilatacijskom kardiomiopatijom. Transkripti za ovaj gen prolaze kroz alternativnu preradu, što rezultira mnogim tkivno specifičnim izoformama, ali priroda pune dužine nekih od ovih varijanti još nije utvrđena.[74] Mutacije ovog gena mogu biti povezane sa blagom ili odsutnom hipertrofijom i dominantnom restriktivnom bolešću, sa visokim rizikom od iznenadne srčane smrti.[73]

Reference

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