CDKAL1

CDKAL1
Identifikatori
Aliasi	CDKAL1
Vanjski ID-jevi	OMIM: 611259 MGI: 1921765 HomoloGene: 9830 GeneCards: CDKAL1
Lokacija gena (čovjek)
Hrom.	Hromosom 6 (čovjek)
Kraj	21,232,404 bp
Lokacija gena (miš)
Hrom.	Hromosom 13 (miš)
Kraj	30,039,657 bp
Ontologija gena
Molekularna funkcija	• aktivnost sa transferazom; • N6-threonylcarbomyladenosine methylthiotransferase activity; • iron-sulfur cluster binding; • vezivanje iona metala; • GO:0001948, GO:0016582 vezivanje za proteine; • catalytic activity; • tRNA (N(6)-L-threonylcarbamoyladenosine(37)-C(2))-methylthiotransferase; • 4 iron, 4 sulfur cluster binding;
Ćelijska komponenta	• integral component of membrane; • rough endoplasmic reticulum; • endoplasmic reticulum membrane; • membrana; • Endoplazmatski retikulum;
Biološki proces	• maintenance of translational fidelity; • tRNA methylthiolation; • tRNA processing; • tRNA modification; • GO:0022610 biološki proces;
	Izvori:Amigo / QuickGO
Ortolozi
	54901
	68916
	ENSG00000145996
	ENSMUSG00000006191
	Q5VV42
	Q91WE6
	NM_017774
	NM_144536; NM_001308486
	NP_060244
	NP_001295415; NP_653119
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

CDKAL1 (eng. sakr. za Cdk5 regulatorno povezani proteinoliki 1) je gen u porodici metiltiotransferaza. Njegove potpune fiziološke funkcije i implikacije nisu u potpunosti utvrđene. Poznato je da CDKAL1 kodira CDK5, protein povezan sa regulatornom podjedinicom 1.^[6] Ovaj protein CDK5 regulatorno je povezan sa podjedinicom proteina 1 nalazi se široko u svim tipovima tkiva, uključujući neuronska i beta-ćelije gušterače.^[7] Sumnja se da je CDKAL1 uključen u put CDK5/p35, u kojem je p35 aktivator za CDK5 koji regulira nekoliko neuronskih funkcija.^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 579 aminokiselina, а molekulska težina 65.111 Da.^[9]

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
MPSASCDTLL	DDIEDIVSQE	DSKPQDRHFV	RKDVVPKVRR	RNTQKYLQEE
ENSPPSDSTI	PGIQKIWIRT	WGCSHNNSDG	EYMAGQLAAY	GYKITENASD
ADLWLLNSCT	VKNPAEDHFR	NSIKKAQEEN	KKIVLAGCVP	QAQPRQDYLK
GLSIIGVQQI	DRVVEVVEET	IKGHSVRLLG	QKKDNGRRLG	GARLDLPKIR
KNPLIEIISI	NTGCLNACTY	CKTKHARGNL	ASYPIDELVD	RAKQSFQEGV
CEIWLTSEDT	GAYGRDIGTN	LPTLLWKLVE	VIPEGAMLRL	GMTNPPYILE
HLEEMAKILN	HPRVYAFLHI	PVQSASDSVL	MEMKREYCVA	DFKRVVDFLK
EKVPGITIAT	DIICGFPGET	DQDFQETVKL	VEEYKFPSLF	INQFYPRPGT
PAAKMEQVPA	QVKKQRTKDL	SRVFHSYSPY	DHKIGERQQV	LVTEESFDSK
FYVAHNQFYE	QVLVPKNPAF	MGKMVEVDIY	ESGKHFMKGQ	PVSDAKVYTP
SISKPLAKGE	VSGLTKDFRN	GLGNQLSSGS	HTSAASQCDS	ASSRMVLPMP
RLHQDCALRM	SVGLALLGLL	FAFFVKVYN

Struktura i funkcija

Strukturno CDKAL1 sadrži skupine gvožđa (Fe) sumpora (S), pa se njegova funkcija može smanjiti inhibicijom biosinteze klastera Fe–S.^[10] Enzimski, CDKAL1 katalizira metiltiolaciju N6-treonilkarbamoil-adenozina 37 (t6A37) u citosolnoj tRNK, za koju je utvrđeno da stabilizuje antikodon-kodonske interakcije tokom translacije.^[11]^[12]

Studije na životinjama

Kod miševa, oštećenje CDKAL1 smanjuje sposobnost jedinke da održava homeostazu glukoze i uzrokuje hipertrofiju otočića ili lezije gušterače.^[13]

Klinički značaj

Kod ljudi je indicirano da je CDKAL1 uključen u dijabetes tipa II. Pokazalo se da CDKAL1 i TCF7L2 smanjuju proizvodnju insulina.^[14] Neka istraživanja pokazuju da varijante CDKAL1 modificiraju tRNK, što rezultira povećanim rizikom od dijabetesa tipa II, kao i gojaznosti.^[15] Varijacije u CDKAL1 također su pripisane razlikama u regulaciji energije. Analiza jednonukleotidnih polimorfizama rezultirala je otkrićem mehanizma odgovora glukoze i insulina prikazanog na slici. Iz tog odnosa je pretpostavljeno da su regulatorni geni CDKAL1 i GIP (insulinotropni polipeptid ovisan o glukozi) povezani sa selektivnošću okoliša i adaptivnom imunošću.^[5]

Studije asocijacija na cijelom genomu povezale su jednonukleotidni polimorfizam u intronu na hromosomu 6 s osjetljivošću na dijabetes tipa 2` (prema RefSeq, maj 2010).^[16]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000145996 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000006191 - 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.
^ ^a ^b Chang CL, Cai JJ, Huang SY, Cheng PJ, Chueh HY, Hsu SY (15. 9. 2014). "Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis". PLOS ONE. 9 (9): e105410. Bibcode:2014PLoSO...9j5410C. doi:10.1371/journal.pone.0105410. PMC 4164438. PMID 25222615.
^ Ching YP, Pang AS, Lam WH, Qi RZ, Wang JH (maj 2002). "Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor". The Journal of Biological Chemistry. 277 (18): 15237–40. doi:10.1074/jbc.C200032200. PMID 11882646.
^ Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, et al. (oktobar 2005). "Cdk5-dependent regulation of glucose-stimulated insulin secretion". Nature Medicine. 11 (10): 1104–8. doi:10.1038/nm1299. PMID 16155576. S2CID 23702471.
^ Takasugi T, Minegishi S, Asada A, Saito T, Kawahara H, Hisanaga S (februar 2016). "Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit, Dependent and Independent of Ubiquitination". The Journal of Biological Chemistry. 291 (9): 4649–57. doi:10.1074/jbc.M115.692871. PMC 4813488. PMID 26631721.
^ "UniProt, Q5VV42" (jezik: engleski). Pristupljeno 30. 9. 2021.
^ Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (januar 2020). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 296. Bibcode:2020NatCo..11..296S. doi:10.1038/s41467-019-14004-5. PMC 6962211. PMID 31941883.
^ Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (januar 2020). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 296. Bibcode:2020NatCo..11..296S. doi:10.1038/s41467-019-14004-5. PMC 6962211. PMID 31941883.
^ Harris KA, Bobay BG, Sarachan KL, Sims AF, Bilbille Y, Deutsch C, et al. (august 2015). "NMR-based Structural Analysis of Threonylcarbamoyl-AMP Synthase and Its Substrate Interactions". The Journal of Biological Chemistry. 290 (33): 20032–43. doi:10.1074/jbc.M114.631242. PMC 4536411. PMID 26060251.
^ Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, et al. (septembar 2011). "Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice". The Journal of Clinical Investigation. 121 (9): 3598–608. doi:10.1172/JCI58056. PMC 3163968. PMID 21841312.
^ Kirchhoff K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, et al. (april 2008). "Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion". Diabetologia. 51 (4): 597–601. doi:10.1007/s00125-008-0926-y. PMID 18264689.
^ Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, et al. (oktobar 2017). "Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue". Molecular Metabolism. 6 (10): 1212–1225. doi:10.1016/j.molmet.2017.07.013. PMC 5641635. PMID 29031721.
^ "Entrez Gene: CDK5 regulatory subunit associated protein 1-like 1". Pristupljeno 12. 3. 2012.

Dopunska literatura

Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. (juni 2007). Wellcome Trust Case Control Consortium (WTCCC). "Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes". Science. 316 (5829): 1336–41. Bibcode:2007Sci...316.1336Z. doi:10.1126/science.1142364. PMC 3772310. PMID 17463249.
Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, et al. (decembar 2007). "Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function". Diabetes. 56 (12): 3101–4. doi:10.2337/db07-0634. PMID 17804762.
Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, et al. (decembar 2007). "Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population". Diabetologia. 50 (12): 2461–6. doi:10.1007/s00125-007-0827-5. PMID 17928989.
Wolf N, Quaranta M, Prescott NJ, Allen M, Smith R, Burden AD, et al. (februar 2008). "Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease". Journal of Medical Genetics. 45 (2): 114–6. doi:10.1136/jmg.2007.053595. PMID 17993580. S2CID 23285801.
Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, et al. (mart 2008). "Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population". Diabetes. 57 (3): 791–5. doi:10.2337/db07-0979. PMID 18162508.
Cauchi S, Proença C, Choquet H, Gaget S, De Graeve F, Marre M, et al. (mart 2008). "Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study". Journal of Molecular Medicine. 86 (3): 341–8. doi:10.1007/s00109-007-0295-x. PMID 18210030. S2CID 21785287.

Vanjski linkovi

Lokacija ljudskog genoma CDKAL1 i stranica sa detaljima o genu CDKAL1 u UCSC Genome Browseru.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000145996 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000006191 - 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.

[:02-5] Chang CL, Cai JJ, Huang SY, Cheng PJ, Chueh HY, Hsu SY (15. 9. 2014). "Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis". PLOS ONE. 9 (9): e105410. Bibcode:2014PLoSO...9j5410C. doi:10.1371/journal.pone.0105410. PMC 4164438. PMID 25222615.

[6] Ching YP, Pang AS, Lam WH, Qi RZ, Wang JH (maj 2002). "Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor". The Journal of Biological Chemistry. 277 (18): 15237–40. doi:10.1074/jbc.C200032200. PMID 11882646.

[7] Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, et al. (oktobar 2005). "Cdk5-dependent regulation of glucose-stimulated insulin secretion". Nature Medicine. 11 (10): 1104–8. doi:10.1038/nm1299. PMID 16155576. S2CID 23702471.

[8] Takasugi T, Minegishi S, Asada A, Saito T, Kawahara H, Hisanaga S (februar 2016). "Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit, Dependent and Independent of Ubiquitination". The Journal of Biological Chemistry. 291 (9): 4649–57. doi:10.1074/jbc.M115.692871. PMC 4813488. PMID 26631721.

[UniProt-9] "UniProt, Q5VV42" (jezik: engleski). Pristupljeno 30. 9. 2021.

[10] Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (januar 2020). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 296. Bibcode:2020NatCo..11..296S. doi:10.1038/s41467-019-14004-5. PMC 6962211. PMID 31941883.

[11] Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (januar 2020). "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification". Nature Communications. 11 (1): 296. Bibcode:2020NatCo..11..296S. doi:10.1038/s41467-019-14004-5. PMC 6962211. PMID 31941883.

[12] Harris KA, Bobay BG, Sarachan KL, Sims AF, Bilbille Y, Deutsch C, et al. (august 2015). "NMR-based Structural Analysis of Threonylcarbamoyl-AMP Synthase and Its Substrate Interactions". The Journal of Biological Chemistry. 290 (33): 20032–43. doi:10.1074/jbc.M114.631242. PMC 4536411. PMID 26060251.

[13] Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, et al. (septembar 2011). "Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice". The Journal of Clinical Investigation. 121 (9): 3598–608. doi:10.1172/JCI58056. PMC 3163968. PMID 21841312.

[14] Kirchhoff K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, et al. (april 2008). "Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion". Diabetologia. 51 (4): 597–601. doi:10.1007/s00125-008-0926-y. PMID 18264689.

[15] Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, et al. (oktobar 2017). "Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue". Molecular Metabolism. 6 (10): 1212–1225. doi:10.1016/j.molmet.2017.07.013. PMC 5641635. PMID 29031721.

[entrez-16] "Entrez Gene: CDK5 regulatory subunit associated protein 1-like 1". Pristupljeno 12. 3. 2012.

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