DYRK1A

DYRK1A
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2VX3, 2WO6, 3ANQ, 3ANR, 4AZE, 4MQ1, 4MQ2, 4NCT, 4YLJ, 4YLK, 4YLL, 4YU2, 5AIK, 5A4Q, 5A4E, 5A3X, 5A4T, 5A54, 5A4L
Identifikatori
Aliasi	DYRK1A
Vanjski ID-jevi	OMIM: 600855 MGI: 1330299 HomoloGene: 55576 GeneCards: DYRK1A
Lokacija gena (čovjek)
Hrom.	Hromosom 21 (čovjek)
Kraj	37,526,358 bp
Lokacija gena (miš)
Hrom.	Hromosom 16 (miš)
Kraj	94,496,376 bp
Obrazac RNK ekspresije
	; ; ; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• transferase activity; • protein kinase activity; • nucleotide binding; • non-membrane spanning protein tyrosine kinase activity; • kinase activity; • protein self-association; • protein serine/threonine kinase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • protein serine/threonine/tyrosine kinase activity; • protein tyrosine kinase activity; • tau protein binding; • ATP binding; • vezivanje identičnih proteina; • tau-protein kinase activity;
Ćelijska komponenta	• nuclear speck; • nukleoplazma; • jedro; • citoplazma; • citoskelet; • Akson; • dendrit; • ribonukleoprotein;
Biološki proces	• positive regulation of protein deacetylation; • Fosforilacija; • regulation of alternative mRNA splicing, via spliceosome; • nervous system development; • protein phosphorylation; • negative regulation of mRNA splicing, via spliceosome; • negative regulation of DNA damage response, signal transduction by p53 class mediator; • GO:0035404 peptidyl-serine phosphorylation; • Jednodnevni biološki ritam; • protein autophosphorylation; • peptidyl-tyrosine phosphorylation; • peptidyl-threonine phosphorylation; • GO:0022415 viral process; • negative regulation of microtubule polymerization; • positive regulation of RNA splicing; • amyloid-beta formation; • peptidyl-serine autophosphorylation; • peptidyl-tyrosine autophosphorylation;
	Izvori:Amigo / QuickGO
Ortolozi
	1859
	13548
	ENSG00000157540
	ENSMUSG00000022897
	Q13627
	Q61214
NM_001396; NM_101395; NM_130436; NM_130437; NM_130438;
	NM_001347721; NM_001347722; NM_001347723
	NM_001113389; NM_007890; NM_001347731
NP_001334650; NP_001334651; NP_001334652; NP_001387; NP_567824;
	NP_569120; NP_569122
NP_001106860; NP_001334660; NP_031916; NP_001389720; NP_001389721;
	NP_001389722
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

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 uredi

Dužina polipeptidnog lanca je 763 aminokiselina, a molekulska težina 85.584 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
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 uredi

DYRK1A 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 uredi

DYRK1A 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 uredi

Pokazalo 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 uredi

Hämmerle B, Elizalde C, Galceran J, et al. (2004). "The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications". J. Neural Transm. Suppl. Journal of Neural Transmission Supplement 67. 67 (67): 129–37. doi:10.1007/978-3-7091-6721-2_11. ISBN 978-3-211-40776-9. PMID 15068245.
Galceran J, de Graaf K, Tejedor FJ, Becker W (2004). "The MNB/DYRK1A protein kinase: genetic and biochemical properties". J. Neural Transm. Suppl. Journal of Neural Transmission Supplement 67. 67 (67): 139–48. doi:10.1007/978-3-7091-6721-2_12. ISBN 978-3-211-40776-9. PMID 15068246.
Schultz SJ, Nigg EA (1994). "Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans". Cell Growth Differ. 4 (10): 821–30. PMID 8274451.
Shindoh N, Kudoh J, Maeda H, et al. (1996). "Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21". Biochem. Biophys. Res. Commun. 225 (1): 92–9. doi:10.1006/bbrc.1996.1135. PMID 8769099.
Guimerá J, Casas C, Pucharcòs C, et al. (1997). "A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region". Hum. Mol. Genet. 5 (9): 1305–10. doi:10.1093/hmg/5.9.1305. PMID 8872470.
Song WJ, Sternberg LR, Kasten-Sportès C, et al. (1997). "Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region"". Genomics. 38 (3): 331–9. doi:10.1006/geno.1996.0636. PMID 8975710.
Ohira M, Seki N, Nagase T, et al. (1997). "Gene identification in 1.6-Mb region of the Down syndrome region on chromosome 21". Genome Res. 7 (1): 47–58. doi:10.1101/gr.7.1.47. PMID 9037601.
Chen H, Antonarakis SE (1997). "Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2". Hum. Genet. 99 (2): 262–5. doi:10.1007/s004390050350. PMID 9048932. S2CID 26729330.
Smith DJ, Stevens ME, Sudanagunta SP, et al. (1997). "Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome". Nat. Genet. 16 (1): 28–36. doi:10.1038/ng0597-28. PMID 9140392. S2CID 29490013.
Dahmane N, Ghezala GA, Gosset P, et al. (1998). "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome". Genomics. 48 (1): 12–23. doi:10.1006/geno.1997.5146. PMID 9503011.
Xu X, Rich ES, Seldin DC (1998). "Murine protein kinase CK2 alpha': cDNA and genomic cloning and chromosomal mapping". Genomics. 48 (1): 79–86. doi:10.1006/geno.1997.5154. PMID 9503019.
Becker W, Weber Y, Wetzel K, et al. (1998). "Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases". J. Biol. Chem. 273 (40): 25893–902. doi:10.1074/jbc.273.40.25893. PMID 9748265.
Wang J, Kudoh J, Shintani A, et al. (1998). "Identification of two novel 5' noncoding exons in human MNB/DYRK gene and alternatively spliced transcripts". Biochem. Biophys. Res. Commun. 250 (3): 704–10. doi:10.1006/bbrc.1998.9392. PMID 9784410.
Guimera J, Casas C, Estivill X, Pritchard M (1999). "Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome". Genomics. 57 (3): 407–18. doi:10.1006/geno.1999.5775. PMID 10329007.
Hattori M, Fujiyama A, Taylor TD, et al. (2000). "The DNA sequence of human chromosome 21". Nature. 405 (6784): 311–9. Bibcode:2000Natur.405..311H. doi:10.1038/35012518. PMID 10830953.
Woods YL, Rena G, Morrice N, et al. (2001). "The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site". Biochem. J. 355 (Pt 3): 597–607. doi:10.1042/bj3550597. PMC 1221773. PMID 11311120.
Mao J, Maye P, Kogerman P, et al. (2002). "Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1". J. Biol. Chem. 277 (38): 35156–61. doi:10.1074/jbc.M206743200. PMID 12138125.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Martí E, Altafaj X, Dierssen M, et al. (2003). "Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system". Brain Res. 964 (2): 250–63. doi:10.1016/S0006-8993(02)04069-6. PMID 12576186. S2CID 35092325.
Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS (2018). "Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors as potential therapeutics". Journal of Medicinal Chemistry. 61 (22): 9791–9810. doi:10.1021/acs.jmedchem.8b00185. PMID 29985601.

Vanjski linkovi uredi

Q13627

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000157540 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000022897 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9284911-5] 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.

[Bol_2011-6] 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.

[entrez-7] "Entrez Gene: DYRK1A dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A".

[pmid19844572-8] 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.

[pmid23160955-9] 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.

[pmid14593110-10] 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.

[pmid32447145-11] 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.

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