Lub luag haujlwm ntawm NEDD4 Subfamily Ntawm HECT E3 Ubiquitin Ligases hauv Neurodevelopment Thiab Neurodegeneration Part 1

Abstract:

Txoj kev ubiquitin tswj kev ua haujlwm ntawm ntau cov proteins thiab tswj cellularprotein homeostasis. Nyob rau hauv xyoo tas los no, nws tau nyiam kev txaus siab rau cov kab mob neurodevelopmental thiab neurodegenerative.

Nrog rau kev txhim kho txuas ntxiv ntawm biotechnology, tib neeg xav paub ntau ntxiv txog kev sib raug zoo ntawm cov cellular proteins thiab nco. Kev tshawb fawb qhia tau hais tias cov protein yog qhov tseem ceeb tshaj plaws biomolecule hauv cov hlwb thiab ua lub luag haujlwm tseem ceeb hauv ntau cov ntaub so ntswg thiab cov kabmob ntawm tib neeg lub cev, thiab nws qhov cuam tshuam rau kev nco tsis tuaj yeem tsis quav ntsej.

Cov protein muaj nyob hauv ntau hom hauv tib neeg lub cev, qhov tseem ceeb tshaj plaws yog cov proteins neuronal. Neuronal proteins yog ib chav kawm ntawm cov proteins uas muaj nyob rau hauv ntau ntau hauv cov neurons thiab yog ib qho tseem ceeb ntawm kev ua haujlwm neuronal. Kev tshawb fawb pom tau tias muaj kev sib txuas zoo ntawm cov proteins neuronal thiab kev nco. Lub synthesis thiab degradation ntawm neuronal proteins yog lub hauv paus rau kev nco. Tsuas yog thaum cov protein synthesis nyob rau hauv lub cell sai tshaj qhov degradation tus nqi nyob rau hauv cov txheej txheem no yuav ua tau zoo nco tau tsim thiab tswj. Yog li ntawd, tswj kev ruaj ntseg ntawm neuronal proteins yog qhov tseem ceeb rau tib neeg lub cim xeeb.

Ntxiv nrog rau cov proteins neuronal, lwm cov proteins hauv lub cev tuaj yeem cuam tshuam kev nco. Piv txwv li, ATP-dependent protein kinase (AMPK) nyob rau hauv lub cellular zog metabolism txoj kev yog ib tug tseem ceeb regulator ntawm intracellular zog metabolism. Cov kev tshawb fawb tau pom tias kev txhawb nqa kev ua haujlwm ntawm AMPK tuaj yeem nce tus nqi ntawm cov protein synthesis hauv lub hlwb, yog li txhim kho kev nco.

Nyob rau tib lub sijhawm, noj qee cov zaub mov uas muaj protein ntau hauv tib neeg lub cev tuaj yeem txhawb nqa cov protein synthesis hauv hlwb, yog li txhim kho kev nco. Piv txwv li, cov ntses uas muaj protein ntau, nqaij, qe, thiab lwm yam khoom noj tuaj yeem muab cov protein zoo rau tib neeg lub cev.

Raws li qhov tshwm sim, muaj kev sib raug zoo ntawm cellular proteins thiab nco. Kev tswj xyuas qhov ruaj khov ntawm cov proteins neuronal thiab txhawb cov protein synthesis hauv cov hlwb yog qhov tseem ceeb heev rau kev txhim kho tib neeg lub cim xeeb. Peb yuav tsum xyuam xim rau kev noj zaub mov, noj cov zaub mov uas muaj cov protein ntau, thiab ntxiv dag zog rau lub cev ua kom lub cev metabolism nrawm, uas yuav pab txhim kho peb lub cim xeeb. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem Paub Short-term Nco yuav ua li cas txhim kho

Ntawm no, peb tau nthuav tawm thawj qhov kev tshuaj xyuas ntawm lub luag haujlwm ntawm 9 cov proteins ntawm HECT E3 ligase NEDD4 subfamily hauv kev txhim kho thiab kev ua haujlwm ntawm cov neurons hauv lub hauv nruab nrab lub paj hlwb (CNS).

Peb tau tham txog lawv cov kev cai thiab lawv txoj kev koom tes ncaj qha lossis tsis ncaj rau cov kab mob hauv lub cev, xws li kev tsis taus ntawm kev txawj ntse, thiab cov kab mob neurodegenerative, xws li Alzheimer's disease, Parkinson's disease, lossis Amyotrophic Lateral Sclerosis.

Cov kev tshawb fawb ntxiv txog kev ua haujlwm ntawm cov proteins no, lawv cov kev tswj hwm, thiab lawv lub hom phiaj hauv neurons yuav ua rau muaj kev nkag siab zoo dua ntawm kev ua haujlwm neuronal thiab tsis ua haujlwm, thiab tseem yuav muab cov ntaub ntawv nthuav dav rau kev txhim kho kev kho mob rau lawv.

Ntsiab lus: ubiquitin; ligases; kev loj hlob; neurodegenerative; kev tsis taus kev txawj ntse; ALS.

1. Taw qhia

Txoj kev loj hlob thiab kev ua haujlwm ntawm lub hauv paus paj hlwb (CNS) yog cov txheej txheem nyuaj uas yuav tsum muaj cov txheej txheem dynamic nrog rau theem ntawm kev loj hlob, kev tsiv teb tsaws, sib txawv, kev loj hlob, thiab synaptic plasticity.

Cov txheej txheem no tau raug tswj kom zoo ua tsaug rau kev koom tes ntawm ntau cov proteins nrog ntau hom cellular localizations androles [1] Kev tswj cov concentrations ntawm cov proteins, hu ua cellular protein homeostasis (proteostasis), yog ua tiav ntawm theem ntawm lawv cov synthesis thiab lawv degradation.

Kev tswj hwm kev ua haujlwm ntawm cov proteins no kuj tseem ceeb heev rau kev txhim kho kom raug thiab ua haujlwm ntawm CNS. Ib feem tseem ceeb ntawm kev tswj hwm no yog pom tau los ntawm kev hloov pauv hloov pauv hloov pauv hloov pauv. Lub ubiquitin (Ub) / Ub-zoo li systems muaj xws li ib tug ntawm lawv [2].

Genesencoding cov tswv cuab ntawm ob lub tshuab no tau cuam tshuam ncaj qha rau hauv cov kab mob neurodevelopmentaldisorders nrog rau kev tsis taus ntawm kev txawj ntse thiab tsis ua haujlwm (RNF12, CUL4B), thiab cov kab mob neurodegenerative, xws li Parkinson's disease (PARK2) lossis AmyotrophicLateral Sclerosis (CCNF) [3–5].

Lub tshuab zoo li Ub / Ub muaj cov txheej txheem intracellular suav nrog 3 chav kawm ntawm cov enzymes, E1, E2, thiab E3 (RING lossis HECT cov tsev neeg) encoded los ntawm ntau dua 700 cov noob hauv humangenome. Txoj hauv kev no ua haujlwm los ntawm kev ntxiv ib lossis ntau qhov me me ubiquitin (76 aa) lossis ubiquitin-zoo li cov proteins (xws li SUMO, Me Ubiquitin MOdifier) ​​rau cov proteins. Raws li kev hloov pauv tom qab kev txhais lus, tagged protein yuav raug xa mus rau proteasome fordegradation lossis yuav muaj nws txoj haujlwm tswj lossis hloov kho [6].

Lub tshuab zoo li Ub / Ub tau kawm ntau xyoo dhau los, tab sis muaj ntau cov lus nug tseem muaj txog lawv txoj cai thiab kev ua haujlwm, cov proteins uas lawv tsom, thiab lawv lub luag haujlwm hauv pathophysiology ntawm tib neeg cov kab mob.

Qhov loj tshaj plaws HECT E3 subfamily yog neuronal precursor cell-expresseddevelopmentally downregulated 4 (NEDD4) subfamily. Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los tham txog lub luag haujlwm ntawm lub cev ntawm CNS ntawm NEDD4 subfamily thiab nws qhov cuam tshuam rau cov kab mob hauv lub cev thiab cov kab mob neurodegenerative.

2. Txheej txheem cej luam ntawm Ubiquitin System

Ubiquitination yog ib qho tseem ceeb hauv kev ua kom cov protein degradation mediated los ntawm proteasome. Nws muaj kev ntxiv ubiquitin (Ub) mus rau lub hom phiaj proteins. Ubiquitin yog 76 aminoacids protein nrog 7 lysine residues siv los txuas lub hom phiaj protein lossis lwm yam Ub (rau polyubiquitination) [7].

Ubiquitin protein tuaj yeem khi rau lub hom phiaj protein raws li ubiquitinmonomer (monoubiquitination) lossis ua ubiquitin polymer (polyubiquitination). Ib qho protein tuaj yeem ua tau ntau yam, uas muaj ntau yam monoubiquitinations ntawm lub hom phiajprotein. Monoubiquitination thiab khi rau ib txoj hlua ntawm ubiquitin txuas los ntawm lysines -63, piv txwv li, yog cov cim qhia txog kev ua haujlwm rau cov protein ubiquitinated.

Kev khi rau achain ntawm lysine-48- txuas ubiquitins yog lub teeb liab rau kev degradation ntawm ubiquitinated protein los ntawm proteasome. Ubiquitinated proteins kuj tuaj yeem deubiquitinated los ntawm txog ahundred deubiquitinating enzymes [8]. Kev sib txawv ntawm cov neeg ua yeeb yam ntawm ubiquitin system thiab kev hloov kho nws tsim cov proteins koom nrog cov txheej txheem no hauv ntau cov txheej txheem ntawm tes, xws li protein homeostasis, endocytosis, intracellular trafficking, cellular stress, thiab autophagy [9–13].

Tsib feem pua ​​​​ntawm cov noob nyob rau hauv tib neeg genome encode proteins ntawm ubiquitin system, uas yog impressive. Ubiquitination ntawm cov protein yog ua tiav los ntawm kev sib koom ua ke ntawm peb chav kawm ntawm enzymes: ubiquitin-activating enzymes (E1), conjugating enzymes (E2), thiabligases (E3).

Ib qho E1 enzyme activates ubiquitin rau kev hloov [14]. Cov enzymes E2, uas muaj 38, ncaj qha hloov ubiquitin mus rau lub hom phiaj proteins nrog kev pab los ntawm athird class ntawm enzymes, lub E3 ligases, uas muaj ib qho Interesting New Gene (RING)domain [15].

Tsev neeg E3 ligases no muaj ntau dua 600 tus tswv cuab. Lwm tsev neeg ntawm E3 yog E3 nrog U-Box sau, E3 nrog RING-nruab nrab-nplhaib (RBR) domain, thiab E3 nrog Homologous rau EA6P C-terminus (HECT) domain [8]. Qee cov E2 enzymes transferubiquitin rau HECT-E3 enzymes, uas tom qab ntawd hloov mus rau lub hom phiaj proteins (Daim duab 1). E3ligases nrog HECT tus lej yog 28 hauv tib neeg. Lawv qhov loj me txawv ntawm 80 txog 500 kDa.

Qhov zoo tshaj plaws ntawm cov enzymes no yog qhov muaj kev txuag C-terminal, catalyticHECT domain ntawm 350 amino acid residues [16]. HECT E3 ligases tau muab faib ua peb tsev neeg: NEDD4, HERC, thiab lwm yam HECT.

Daim duab 1. Schematic sawv cev ntawm cov txheej txheem ubiquitination los ntawm E3 ligases uas muaj HECT domain. Ubiquitin yog qhib los ntawm ib qho enzyme E1 thiab tom qab ntawd hloov mus rau E2 enzymes thiab HECT E3enzyme.

E3 enzyme hloov ubiquitin mus rau lub hom phiaj protein, ua rau nws cov monoubiquitination orpolyubiquitination. Lub E3 ligase muaj 3 lub npe, N-terminal C2 domain, WW nplua nuj domain thiab C-terminal domain koom ua ob lub lobes (N-lobe thiab C-lobe).

3. NEDD4 E3 Ligases Subfamily

3.1. Structure thiab Diversity

NEDD4 subfamily muaj nyob thoob plaws hauv eukaryotes. Nws suav nrog cuaj E3 ligases NEDD4-1, NEDD4-2, ITCH, WWP1, WWP2, SMURF1, SMURF2, NEDL1, thiab sib koom cov qauv sib txawv uas tshwm sim los ntawm muaj 3 qhov sib txawv khaws cia thaum lub sij hawm mammalian evolution: ib N-terminal C2 domain, ob mus rau plaub tryptophan. tryptophan (WW) domains, thiab HECT domains (Daim duab 1).

C2 domain tuaj yeem khi rau phospholipids hauv calcium-dependent yam. Raws li qhov tshwm sim, proteins con. Kev cob qhia C2 tuaj yeem kho cov phiaj xwm hauv lub cev ntawm cov plasma membrane, endosomes, thiab multivesicular lub cev [17].

Nws tau piav qhia thawj zaug hauv cov protein kinase C (PKC) thiab yog tsim los ntawm 8 beta-strands uas tuaj yeem ua haujlwm ob lossis peb lub calcium ions. WW domains, uas muaj nyob rau nruab nrab 40 amino acids nrog ob invariant tryptophan residues koom nrog cov protein / protein sib cuam tshuam. Kev sib cuam tshuam yog ua tiav nrog proline-nplua nuj motifs (PY lossis PPxY) tam sim no ntawm lub hom phiaj proteins. 

Qhov kev khi tshwj xeeb ntawm WW domain los ntawm nws cov t-stranded folding ntawm cov residues tam sim no nyob rau hauv lub loops uas txuas lawv. C-terminal HECT domain yog E3 catalytic domain nrog lub xub ntiag ntawm catalytic cysteine. Nws muaj qhov loj me ntawm li 350 amino acids tsim nyob rau hauv ob lub lobes, N-lobe thiab C-lobe.

N-lobe khi rau E2 enzyme-ubiquitin complex, tso cai rau kev hloov ntawm ubiquitin protein los ntawm E2 mus rau C-lobe ntawm thioester intermediate nrog cov catalytic cysteine. Thaum ubiquitin hloov mus rau C-lobe, nws tuaj yeem hloov mus rau lub hom phiaj protein (Daim duab 1). Cov 3 qhov no tau txawv txav thaum lub sij hawm mammalian evolution (Daim duab 2).

3.2. Muaj nuj nqi thiab kev cai

9 cov tswv cuab ntawm NEDD4 subfamily khi ib qho tseem ceeb ntawm cov proteins lub hom phiaj thiab cuam tshuam rau ntau yam txheej txheem ntawm tes.

Cov proteins Neural precursor cell. tau nthuav tawm Developmentally Down-regulated protein 4 naj npawb 1 (NEDD4-1) thiab tus naj npawb 2 (NEDD4-2) yog thawj cov tswv cuab uas raug tshawb pom hauv tsev neeg no thiab tam sim no yog cov neeg kawm ntau tshaj plaws.

NEDD4-1 tau nthuav tawm thoob plaws ntiaj teb thiab koom nrog ntau lub cev ntawm tib neeg lub luag haujlwm cuam tshuam nrog ntau lub hom phiaj proteins. Ntawm cov hom phiaj protein no yog PTEN, Akt, Beclin1, lossis FGFRl, uas txhais tau hais tias NEDD4-1 kev koom tes hauv cell proliferation, sib txawv, tsiv teb tsaws, thiab ntxeem tau, tab sis kuj apoptosis, autophagy, thiab DNA puas teb. Tus tswv cuab ntawm tsev neeg pab nyiaj tau xav tias yuav cuam tshuam rau ntau yam kab mob, los ntawm cov qog nqaij hlav mus rau cov kab mob neurodegenerative [18].

NEDD4-2 yog ib qho E3 ligase rau ntau ion channels, suav nrog sodium, chloride, thiab potassium channels, xws li epithelial Na+ channel EnaC, uas cuam tshuam nrog sodium thiab nqus dej hauv lub ntsws, lub raum, thiab txoj hnyuv [{ {3}}].

Nws tswj hwm EnaC muaj nuj nqi los ntawm kev khi rau nws cov PY motifs tswj cov naj npawb ntawm cov xov tooj ntawm tes 22,23. Nws kuj cuam tshuam nrog cov proteins uas cuam tshuam rau hauv Wnt signaling pathway, TGF- signaling pathway, thiab autophagy [24–26].

Txoj cai ntawm NEDD4-2 kev ua haujlwm tuaj yeem kho tau los ntawm phosphorylation [27–29]. Piv txwv li, nws cov phosphorylation los ntawm RAC-alpha serine / threonine kinase protein 1 (AKT1) thiab cov ntshav thiab glucocorticoid-regulated kinase 1 (SGK1) ua rau kev nrhiav neeg ua haujlwm ntawm theadaptor protein 14.3.3 uas cuam tshuam nrog ENaC [27]. Lub phosphorylation ntawm NEDD4-2 kuj cuam tshuam nrog ORAI khi, uas cuam tshuam rau cov cim qhia calcium [30].

Interestingly, theC2 domain of NEDD4-1 and NEDD4-2 acts as an autoinhibitory domain of the E3 ligaseactivity. Calcium, los ntawm kev khi rau C2 tus thawj coj, tso tawm qhov no autoinhibition.The Itchy E3 Ubiquitin Protein Ligase Homolog protein (ITCH) tswj cov kab mob loj ntawm cov txheej txheem lom neeg vim muaj ntau dua 50 lub hom phiaj proteins, suav nrog Jun proteins thiab ob tus tswv cuab ntawm p53 tsev neeg, p63 thiab p73 [31–33].

ITCH plays lub luag haujlwm hauv kev tswj hwm ntawm TGF- taw qhia txoj hauv kev thiab ua rau cov qog nqaij hlav [34,35]. Nws cuam tshuam rau lwm txoj hauv kev tseem ceeb, xws li Hedgehog, Hippo, Wnt, thiab Notch signaling pathways [36–39].Nws koom nrog hauv kev ua haujlwm endosomal thiab lysosomal, thiab DNA kev puas tsuaj teb [31,40,41].

Kev tswj hwm ntawm ICTH kev ua haujlwm tuaj yeem tau txais los ntawm kev khi rau cov protein, xws li N4BP1 uas cuam tshuam nrog WW2 domain ntawm ITCH impeding kev cuam tshuam nrog nws lub hom phiaj protein (p73a, JUN, p63).

Phosphorylation ntawm ITCH los ntawm JNK1 activates cov protein.Lub WW-domain uas muaj Protein 1 (WWP1) yog ib tug multifunctional protein ntau lub hom phiaj, xws li Smad2, Smad4, ErbB4 / HER4, JunB thiab p53. Yog li ntawd, WWP1 muaj lub luag haujlwm hauv kev sau ntawv, kev lag luam protein, kev puas tsuaj rau cov protein, apoptosis, thiab kis kab mob, thiab lwm yam. Nws tau cuam tshuam rau cov qog nqaij hlav, xws li cov hnyuv thiab lub mis, cov kab mob sib kis, thiab cov kab mob neurological [42].

Nws khi rau nws lub hom phiaj proteinsmainly los ntawm nws lub npe WW. Txawm li cas los xij, nws khi rau p53 ntawm nws tus kheej ntawm WW domain.Qhov kev sib cuam tshuam zoo tswj hwm thiab ruaj khov p53 thiab yog li ua rau apoptosis [43].WWP2 yog lwm E3 ligase ntawm no subfamily uas khi rau lub hom phiaj koom nrog hauv txoj kev sib txawv, xws li PI3K / Akt. los yog TGF- pathways. Nws kuj khi rau thiab txo qis ENaC [44] thiab ubiquitinates RNA polymerase II [45].

Vim nws muaj ntau hom kev ua haujlwm, WWP2 tau cuam tshuam rau hauv cov qog nqaij hlav thiab kev hloov kho ntawm lub cev tiv thaiv kab mob [46] .Lub SMAD Ubiquitylation Regulatory Factor 1 thiab 2 (SMURF1 thiab SMURF2) tau pom thawj zaug raws li E3 ligases muaj peev xwm ntawm kev tswj tsis zoo ntawm TGF-/BMP signaling. [47, 48]. Txawm li cas los xij, lawv kuj tseem cuam tshuam rau lwm cov txheej txheem.

SMURF1 lub hom phiaj rau txoj kev Wnt uas tsis yog txoj hauv kev thiab txoj hauv kev MAPK [49]. Raws li, SMURF1 koom nrog hauv kev tswj hwm ntawm cell loj hlob thiab morphogenesis, cell migration, polarity, thiab autophagy.

Nws txoj haujlwm catalytic tuaj yeem txhim kho los ntawm kev khi rau casein kinase 2-kev cuam tshuam cov protein 1 (CKIP1) los ntawm nws lub npe WW [50]. SMURF1 tseem tswj hwm p53 kev ua haujlwm, ywj siab ntawm nws txoj haujlwm enzymatic, los ntawm kev khi rau lwm qhov E3 ligase, MDM2, uas nws qhov kev ua haujlwm ntawm lub cev yuav nce ntxiv.

MDM2 yog RING-E3 ligase uas yuav tsom p53 fordegradation los ntawm proteasome [51]. SMURF2 cuam tshuam nrog cov txheej txheem zoo sib xws. Nws dualrole hauv kev mob qog noj ntshav feem ntau tau tham txog vim nws tuaj yeem ua ob qho tib si raws li cov qog nqaij hlav thiab cov activator. Nws kuj tseem koom nrog hauv genomic stability los ntawm kev ua ntawm chromatin thiab apoptosis [49].

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