CDKAL1

CDKAL1 (Cdk5 regulatory associated protein 1-like 1) is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1.[6] This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells.[7] CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.[8]

Figure 1: Schematic of CDKAL1 involvement with Insulin and Glucose regulation.[1]
CDKAL1
Identifiers
AliasesCDKAL1, CDK5 regulatory subunit associated protein 1 like 1
External IDsOMIM: 611259 MGI: 1921765 HomoloGene: 9830 GeneCards: CDKAL1
Gene location (Human)
Chr.Chromosome 6 (human)[2]
Band6p22.3Start20,534,457 bp[2]
End21,232,404 bp[2]
Orthologs
SpeciesHumanMouse
Entrez

54901

68916

Ensembl

ENSG00000145996

ENSMUSG00000006191

UniProt

Q5VV42

Q91WE6

RefSeq (mRNA)

NM_017774

NM_144536
NM_001308486

RefSeq (protein)

NP_060244

NP_001295415
NP_653119

Location (UCSC)Chr 6: 20.53 – 21.23 MbChr 13: 29.19 – 29.86 Mb
PubMed search[4][5]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function

Structurally CDKAL1 contains two iron (Fe) sulfur (S) clusters, therefore its function can be reduced by inhibiting Fe-S cluster biosynthesis.[9] Enzymatically, CDKAL1 catalyzes methylthiolation of N6-threonylcarbamoyl adenosine 37 (t6A37) in cytosolic tRNA, which has been determined to stabilize anticodon-codon interactions during translation.[10][11]

Clinical significance

In humans, CDKAL1 is indicated to be involved in type II diabetes. CDKAL1 and TCF7L2 have been shown to reduce the production of insulin.[12] Some studies indicate that CDKAL1 variants modify tRNA resulting in increased risks of type II diabetes as well as obesity.[13] Variation in CDKAL1 was also attributed to differences in energy regulation. Single nucleotide polymorphism analysis resulted in the discovery of the mechanism of glucose and insulin responses demonstrated in the figure. From this relationship, it has been hypothesized that the regulatory genes CDKAL1 and GIP(glucose-dependent insulinotropic polypeptide) are related to environmental selectivity and adaptive immunity.[1]

Genome-wide association studies have linked single nucleotide polymorphisms in an intron on chromosome 6 with susceptibility to type 2 diabetes`. [provided by RefSeq, May 2010].[14]

Animal studies

In mice, CDKAL1 impairment reduces the mouse's ability to maintain glucose homeostasis and causes pancreatic islet hypertrophy, or pancreatic lesions.[15]

References
  1. Chang CL, Cai JJ, Huang SY, Cheng PJ, Chueh HY, Hsu SY (2014-09-15). "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.
  2. GRCh38: Ensembl release 89: ENSG00000145996 - Ensembl, May 2017
  3. GRCm38: Ensembl release 89: ENSMUSG00000006191 - Ensembl, May 2017
  4. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. Ching YP, Pang AS, Lam WH, Qi RZ, Wang JH (May 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. (October 2005). "Cdk5-dependent regulation of glucose-stimulated insulin secretion". Nature Medicine. 11 (10): 1104–8. doi:10.1038/nm1299. PMID 16155576.
  8. Takasugi T, Minegishi S, Asada A, Saito T, Kawahara H, Hisanaga S (February 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.
  9. Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (January 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.
  10. Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, et al. (January 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. PMID 31941883.
  11. 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.
  12. 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.
  13. Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, et al. (October 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.
  14. "Entrez Gene: CDK5 regulatory subunit associated protein 1-like 1". Retrieved 2012-03-12.
  15. Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, et al. (September 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.

Further reading
  • Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. (June 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. (December 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. (December 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. (February 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.
  • Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, et al. (March 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. (March 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.


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