DYRK1A
Dvospecifična, tirozinskom fosforilcijom regulirana kinaza 1A jest enzim koji je kod ljudi kodiran genom DYRK1A sa hromosoma 21.[5] Alternativna prerada ovog gena generira nekoliko varijanti transkripta koje se međusobno razlikuju jedna od druge bilo u 5' UTR ili u 3' UTR kodirajućoj regiji.[6] Ove varijante transkripta kodiraju najmanje pet različitih izoformi.[7]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 763 aminokiselina, a molekulska težina 85.584 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MHTGGETSAC | KPSSVRLAPS | FSFHAAGLQM | AGQMPHSHQY | SDRRQPNISD | ||||
| QQVSALSYSD | QIQQPLTNQV | MPDIVMLQRR | MPQTFRDPAT | APLRKLSVDL | ||||
| IKTYKHINEV | YYAKKKRRHQ | QGQGDDSSHK | KERKVYNDGY | DDDNYDYIVK | ||||
| NGEKWMDRYE | IDSLIGKGSF | GQVVKAYDRV | EQEWVAIKII | KNKKAFLNQA | ||||
| QIEVRLLELM | NKHDTEMKYY | IVHLKRHFMF | RNHLCLVFEM | LSYNLYDLLR | ||||
| NTNFRGVSLN | LTRKFAQQMC | TALLFLATPE | LSIIHCDLKP | ENILLCNPKR | ||||
| SAIKIVDFGS | SCQLGQRIYQ | YIQSRFYRSP | EVLLGMPYDL | AIDMWSLGCI | ||||
| LVEMHTGEPL | FSGANEVDQM | NKIVEVLGIP | PAHILDQAPK | ARKFFEKLPD | ||||
| GTWNLKKTKD | GKREYKPPGT | RKLHNILGVE | TGGPGGRRAG | ESGHTVADYL | ||||
| KFKDLILRML | DYDPKTRIQP | YYALQHSFFK | KTADEGTNTS | NSVSTSPAME | ||||
| QSQSSGTTSS | TSSSSGGSSG | TSNSGRARSD | PTHQHRHSGG | HFTAAVQAMD | ||||
| CETHSPQVRQ | QFPAPLGWSG | TEAPTQVTVE | THPVQETTFH | VAPQQNALHH | ||||
| HHGNSSHHHH | HHHHHHHHHG | QQALGNRTRP | RVYNSPTNSS | STQDSMEVGH | ||||
| SHHSMTSLSS | STTSSSTSSS | STGNQGNQAY | QNRPVAANTL | DFGQNGAMDV | ||||
| NLTVYSNPRQ | ETGIAGHPTY | QFSANTGPAH | YMTEGHLTMR | QGADREESPM | ||||
| TGVCVQQSPV | ASS |
Funkcija
urediDYRK1A je član porodice kinaza reguliranih fosforilacijom tirozina, s dvostrukom specifičnošću (DYRK). Ovaj član sadrži jedarnu ciljnu signalnu sekvencu, protein kinazni domen, motiv leucinskog zatvarača i visoko konzervativno 13-uzastopno-histidinsko ponavljanje. Katalizira svoju autofosforilaciju na serinskim/treoninskim i tirozinskikm ostacima. Može imati značajnu ulogu u signalnom putu koji regulira proliferaciju ćelija i može biti uključen u razvoj mozga. Ovaj gen je homolog drozofilskog gena mnb (minibrain) i pacovskog Dyrk gena.[7]
Također je pokazano da Dyrk1a modulira nivo homocisteina u plazmi u mišjem modelu prekomjerne ekspresije.[8]
Klinički značaj
urediDYRK1A je lokaliziran u kritičnom području hromosoma 21 za Downov sindrom i smatra se da je jak kandidat gen za defekte u učenju povezane s Downovim sindromom.[7] Osim toga, otkriveno je da jednonukleotidni polimorfizam (SNP) u DYRK1A je povezan s replikacijom HIV-1 u makrofagima izvedenim iz monocita, kao i sa sporijom progresijom do AIDS-a u dvije nezavisne kohorte osoba zaraženih HIV-1.[6] Mutacije u DYRK1A također su povezane sa poremećajem iz spektra autizma.[9]
Interakcije
urediPokazalo se da DYRK1A reaguje sa WDR68.[10]
U kompjuterskoj analizi, spojevi iz biblioteke sintetizovanih pirolonom fuzijom spojeva benzosuberena pokazala su veću efikasnost liganda, afinitet vezivanja, efikasnost lipofilnog liganda i povoljne vrednosti torzije, u poređenju sa 2C3 (kokristalizirani spoj). [11]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000157540 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022897 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Guimera J, Pritchard M, Nadal M, Estivill X (Sep 1997). "Minibrain (MNBH) is a single copy gene mapping to human chromosome 21q22.2". Cytogenet Cell Genet. 77 (3–4): 182–4. doi:10.1159/000134571. PMID 9284911.
- ^ a b Bol SM, Moerland PD, Limou S, van Remmerden Y, Coulonges C, van Manen D, Herbeck JT, Fellay J, Sieberer M, Sietzema JG, van 't Slot R, Martinson J, Zagury JF, Schuitemaker H, van 't Wout AB (2011). "Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages". PLOS ONE. 6 (2): e17190. Bibcode:2011PLoSO...617190B. doi:10.1371/journal.pone.0017190. PMC 3045405. PMID 21364930.
- ^ a b c d "Entrez Gene: DYRK1A dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A".
- ^ Noll C, Planque C, Ripoll C, Guedj F, Diez A, Ducros V, Belin N, Duchon A, Paul JL, Badel A, de Freminville B, Grattau Y, Bléhaut H, Herault Y, Janel N, Delabar JM (2009). "DYRK1A, a novel determinant of the methionine-homocysteine cycle in different mouse models overexpressing this Down-syndrome-associated kinase". PLOS ONE. 4 (10): e7540. Bibcode:2009PLoSO...4.7540N. doi:10.1371/journal.pone.0007540. PMC 2760102. PMID 19844572.
- ^ O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J (December 2012). "Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders". Science. 338 (6114): 1619–22. Bibcode:2012Sci...338.1619O. doi:10.1126/science.1227764. PMC 3528801. PMID 23160955.
- ^ Skurat AV, Dietrich AD (January 2004). "Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases". J. Biol. Chem. 279 (4): 2490–8. doi:10.1074/jbc.M301769200. PMID 14593110.
- ^ Bhardwaj VK, Singh R, Sharma J, Das P, Purohit R (October 2020). "Structural based study to identify new potential inhibitors for dual specificity tyrosine-phosphorylation- regulated kinase". Computer Methods Programs in Biomedicine. 194 (1): 105494. doi:10.1016/j.cmpb.2020.105494. PMID 32447145. S2CID 218874460.
Dopunska literatura
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