CDKAL1 explained

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.^[1] This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells.^[2] CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.^[3]

Structure and function

Structurally CDKAL1 contains two iron (Fe) sulfur (S) clusters, therefore its function can be reduced by inhibiting Fe-S cluster biosynthesis.^[4] Enzymatically, CDKAL1 catalyzes methylthiolation of N6-threonylcarbamoyl adenosine 37 (t6A37) in cytosolic tRNA, which has been determined to stabilize anticodon-codon interactions during translation.^{[5] [6]}

Clinical significance

In humans, CDKAL1 is indicated to be involved in type II diabetes. Mutations in CDKAL1 and TCF7L2 have been associated with low production of insulin.^[7] Some studies indicate that CDKAL1 variants modify tRNA resulting in increased risks of type II diabetes as well as obesity.^[8] 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.

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].^[9]

Animal studies

In mice, CDKAL1 impairment reduces the mouse's ability to maintain glucose homeostasis and causes pancreatic islet hypertrophy, or pancreatic lesions.^[10]

Further reading

• Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, McCarthy MI, Hattersley AT . 6 . Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes . Science . 316 . 5829 . 1336–41 . June 2007 . 17463249 . 3772310 . 10.1126/science.1142364 . Eleftheria Zeggini . Wellcome Trust Case Control Consortium (WTCCC) . 2007Sci...316.1336Z .
• Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, Frayling TM, Walker M . 6 . 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 . December 2007 . 17804762 . 10.2337/db07-0634 . free . U.K. Type 2 Diabetes Genetics Consortium .
• Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, Froguel P, Kadowaki T . 6 . Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population . Diabetologia . 50 . 12 . 2461–6 . December 2007 . 17928989 . 10.1007/s00125-007-0827-5 . free .
• Wolf N, Quaranta M, Prescott NJ, Allen M, Smith R, Burden AD, Worthington J, Griffiths CE, Mathew CG, Barker JN, Capon F, Trembath RC . 6 . Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease . Journal of Medical Genetics . 45 . 2 . 114–6 . February 2008 . 17993580 . 10.1136/jmg.2007.053595 . 23285801 .
• Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, Kawamori R, Nakamura Y, Maeda S . 6 . 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 . March 2008 . 18162508 . 10.2337/db07-0979 . free .
• Cauchi S, Proença C, Choquet H, Gaget S, De Graeve F, Marre M, Balkau B, Tichet J, Meyre D, Vaxillaire M, Froguel P . 6 . 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 . March 2008 . 18210030 . 10.1007/s00109-007-0295-x . 21785287 .

Notes and References

1. Ching YP, Pang AS, Lam WH, Qi RZ, Wang JH . Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor . The Journal of Biological Chemistry . 277 . 18 . 15237–40 . May 2002 . 11882646 . 10.1074/jbc.C200032200 . free .
2. Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, Yamada Y, Mikoshiba K, Seino Y, Matsui H, Tomizawa K . 6 . Cdk5-dependent regulation of glucose-stimulated insulin secretion . Nature Medicine . 11 . 10 . 1104–8 . October 2005 . 16155576 . 10.1038/nm1299 . 23702471 .
3. Takasugi T, Minegishi S, Asada A, Saito T, Kawahara H, Hisanaga S . 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 . February 2016 . 26631721 . 4813488 . 10.1074/jbc.M115.692871 . free .
4. Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, Rathkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, de Angelis MH, Cai WM, Rajan M, Hu J, Dedon PC, Leibold EA . 6 . Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification . Nature Communications . 11 . 1 . 296 . January 2020 . 31941883 . 6962211 . 10.1038/s41467-019-14004-5 . 2020NatCo..11..296S .
5. Santos MC, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, Rathkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, de Angelis MH, Cai WM, Rajan M, Hu J, Dedon PC, Leibold EA . 6 . Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification . Nature Communications . 11 . 1 . 296 . January 2020 . 31941883 . 10.1038/s41467-019-14004-5 . 2020NatCo..11..296S . free . 6962211 .
6. Harris KA, Bobay BG, Sarachan KL, Sims AF, Bilbille Y, Deutsch C, Iwata-Reuyl D, Agris PF . 6 . NMR-based Structural Analysis of Threonylcarbamoyl-AMP Synthase and Its Substrate Interactions . The Journal of Biological Chemistry . 290 . 33 . 20032–43 . August 2015 . 26060251 . 4536411 . 10.1074/jbc.M114.631242 . free .
7. Kirchhoff K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, Stefan N, Häring HU, Fritsche A . 6 . Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion . Diabetologia . 51 . 4 . 597–601 . April 2008 . 18264689 . 10.1007/s00125-008-0926-y . free .
8. Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, Deng Z, LeClair KB, Hall JA, Hong S, Zushin PH, Smith KL, Gygi SP, Hagen S, Cohen DE, Banks AS . 6 . Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue . Molecular Metabolism . 6 . 10 . 1212–1225 . October 2017 . 29031721 . 5641635 . 10.1016/j.molmet.2017.07.013 .
9. Web site: Entrez Gene: CDK5 regulatory subunit associated protein 1-like 1. 2012-03-12 .
10. Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, Matsui H, Atta M, Michiue H, Fontecave M, Yamagata K, Suzuki T, Tomizawa K . 6 . 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 . September 2011 . 21841312 . 10.1172/JCI58056 . 3163968 .