Glucokinase Regulatory Protein

From Proteopedia

PDB ID 4BB9

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1 Glucokinase (Hexokinase 4) Regulatory Protein
2 Disease
3 Glucokinase Regulatory Protein Structure
4 Regulation Mechanism

Glucokinase (Hexokinase 4) Regulatory Protein

Glucokinase regulatory protein is also known as glucokinase (hexokinase 4) regulator. This protein is important in the metabolism of glucose in the body. It maintains the location and activity of the enzyme glucokinase (hexokinase 4). Regulation occurs through competitive inhibition of glucokinase. The regulating protein binds to glucokinase, thus inhibiting glucokinase's activity. The regulatory protein is not present in the liver, where it's substrate is bio-synthesized.^[1] Conversely, the regulatory protein is present in liver cells where glucokinase is synthesized.

Disease

GCKR variants affect the glucose and lipid homeostasis and are associated with hypertriglyceridaemia^[2]. Mutations in glucokinase regulatory protein can contribute to type 2 diabetes and hyperinsulinemic hypoglycemia. Both of these health issues involve either high or low levels of blood glucose.^[3]

Glucokinase Regulatory Protein Structure

This protein is made up of 626 amino acids, and it weighs 68 kDa.^[4] This protein is trilobal, with two identical sugar isomerase (SIS) domains , and one . The sugar isomerase domains are dominated by 5 stranded parallel beta-sheets that are flanked on either side by alpha-helices, Effectively making an .

The lid domain consists of seven alpha-helices, with a triple helical core. The core is flanked by a single helix that runs parallel to the triple helix. The remaining helices run perpendicular to the triple helix. There are 14 residues that act as links between the domains.^[5]

Regulation Mechanism

In the presence of fructose 6-phosphate, glucokinase regulatory protein is activated and releases the enzyme glucokinase. Fructose 6-phosphate is produced when glucose is present in concentrations higher than will be immediately digested. The regulatory protein is also antagonized by . In essence, the regulatory protein is activated when glucose is ready to be stored, and inactivated when the storage process is complete. ^[6]

Gluokinase regulatory protein controls the location of glucokinase, which is important in the digestion of glucose. The enzyme phosphorylates glucose, in preparation for storage in the form of glycogen.^[5]^[7]

3D structures of glucokinase regulatory protein

Updated on 31-March-2019

4bb9 – hGKRP (mutant) + fructose-1-phosphate – human
4bba – hGKRP (mutant) + phosphate
4ly9 – hGKRP + sorbitol-6-phosphate + piperazine derivative
4mqu, 4mro – hGKRP + piperazine derivative + glucitol derivative
4msu, 4ohk, 4ohm, 4oho, 4ohp, 4olh – hGKRP + piperazine derivative + sorbitol-6-phosphate
4op1, 4op2, 4op3, 4pxs – hGKRP + pyridine derivative + sorbitol-6-phosphate
4px2, 4px3, 4px5 – hGKRP + sulfonamide derivative + sorbitol-6-phosphate
3w0l – GKRP + glucokinase – Xenopus laevis
4lc9 – GKRP + glucokinase – rat

References

↑ Van Schaftingen E. Short-term regulation of glucokinase. Diabetologia. 1994 Sep;37 Suppl 2:S43-7. PMID:7821739
↑ Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012 Mar;55(3):781-9. doi: 10.1002/hep.24806. Epub 2011 Dec 18. PMID:22105854 doi:http://dx.doi.org/10.1002/hep.24806
↑ de la Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart JJ, Ferrer JC. Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase. FEBS Lett. 1999 Aug 6;456(2):332-8. PMID:10456334
↑ Van Schaftingen E. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate. Eur J Biochem. 1989 Jan 15;179(1):179-84. PMID:2917560
↑ ^5.0 ^5.1 Pautsch A, Stadler N, Lohle A, Rist W, Berg A, Glocker L, Nar H, Reinert D, Lenter M, Heckel A, Schnapp G, Kauschke SG. Crystal Structure of Glucokinase Regulatory Protein. Biochemistry. 2013 May 9. PMID:23621087 doi:10.1021/bi4000782
↑ Mukhtar MH, Payne VA, Arden C, Harbottle A, Khan S, Lange AJ, Agius L. Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R766-74. doi:, 10.1152/ajpregu.00593.2007. Epub 2008 Jan 16. PMID:18199594 doi:http://dx.doi.org/10.1152/ajpregu.00593.2007
↑ Pino MF, Kim KA, Shelton KD, Lindner J, Odili S, Li C, Collins HW, Shiota M, Matschinsky FM, Magnuson MA. Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations. J Biol Chem. 2007 May 4;282(18):13906-16. Epub 2007 Mar 12. PMID:17353190 doi:http://dx.doi.org/10.1074/jbc.M610094200