Glucokinase regulatory protein

Glucokinase (GK) in liver cells phosphorylates glucose, preparing it for incorporation into glycogen or for glycolysis. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring.{{cite journal | vauthors = Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA | title = Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition | journal = International Journal of Experimental Diabetes Research | volume = 2 | issue = 3 | pages = 173–86 | year = 2001 | pmid = 12369705 | pmc = 2478546 | doi = 10.1155/EDR.2001.173 | doi-access = free }} As the glucose supply declines during periods of fasting, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form.{{cite journal | vauthors = Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA | title = Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 52 | pages = 37125–30 | date = December 1999 | pmid = 10601273 | doi = 10.1074/jbc.274.52.37125 | doi-access = free }} As glucose and insulin levels rise, as during digestion of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the bifunctional enzyme.{{cite journal | vauthors = Payne VA, Arden C, Wu C, Lange AJ, Agius L | title = Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes | journal = Diabetes | volume = 54 | issue = 7 | pages = 1949–57 | date = July 2005 | pmid = 15983194 | doi = 10.2337/diabetes.54.7.1949 | url = http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=15983194 | doi-access = free }}

In hepatocytes of various mammals, GKRP has always been found in molar excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton.{{cite book | vauthors = van Schaftingen EF, Veiga da Cunha M | veditors = Matschinsky M |title= in Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes) |publisher=S. Karger AG (Switzerland) |year=2004 |pages=197–307 |chapter=Discovery and role of glucokinase regulatory protein |isbn=978-3-8055-7744-1 }}

GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm.

File:GKRP Chain A, F6P binding site.png

GKRP itself is subject to modulation. Fructose and sorbitol can both be converted to fructose-1-phosphate, which inhibits GKRP and frees GK. Fructose 6-phosphate (F6P) binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. F6P induces a conformational change in GKRP which promotes the formation of the glucokinase-GKRP complex, thereby increasing the ability of GKRP to inhibit glucokinase. Residues Ser110, Ser179, Lys514, and Thr109 (using amino acid numbering based on the Homo sapiens GKRP sequence) within the binding site for F6P were determined to be critical to the ability of F6P to induce this conformational change in GKRP. Mutations of these residues resulted in proteins that were 5-fold (S110), 10-fold (T109), and 50-fold (S179 and K514) less effective inhibitors glucokinase and had significantly reduced affinity for F6P. {{cite journal |last1=Veiga-da-Cunha |first1=Maria |last2=Van Schaftingen |first2=Emile |title=Identification of Fructose 6-Phosphate- and Fructose 1-Phosphate-binding Residues in the Regulatory Protein of Glucokinase* |journal=Journal of Biological Chemistry |date=8 March 2002 |volume=277 |issue=10 |pages=8466–8473 |doi=10.1074/jbc.M105984200 |doi-access=free |pmid=11756407 |issn=0021-9258}}In contrast, phosphorylation of GKRP by AMP-activated protein kinase, induced by elevated levels of AMP, reduces its capacity to inactivate GK.{{cite journal | vauthors = Mukhtar MH, Payne VA, Arden C, Harbottle A, Khan S, Lange AJ, Agius L | title = 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 | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 294 | issue = 3 | pages = R766-74 | date = March 2008 | pmid = 18199594 | doi = 10.1152/ajpregu.00593.2007 }}

A presence and role of GKRP in other organs and tissues beyond the liver remains uncertain. Some researchers have finding small amounts of GKRP, or at least RNA coding for it, in small amounts in certain rat lung cells, in pancreatic islet cells, and in periventricular neurons of the hypothalamus in rats,{{cite journal | vauthors = Alvarez E, Roncero I, Chowen JA, Vázquez P, Blázquez E | title = Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain | journal = Journal of Neurochemistry | volume = 80 | issue = 1 | pages = 45–53 | date = January 2002 | pmid = 11796742 | doi = 10.1046/j.0022-3042.2001.00677.x | s2cid = 46075589 | doi-access = free }} but physiological function and significance in these organs are unknown.

GKRP was originally discovered in rat liver. GKRP was found to serve a similar function in livers of mice and humans as well as other animals.{{cite journal | vauthors = Polakof S, Míguez JM, Soengas JL | title = A hepatic protein modulates glucokinase activity in fish and avian liver: a comparative study | journal = Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology | volume = 179 | issue = 5 | pages = 643–52 | date = July 2009 | pmid = 19247671 | doi = 10.1007/s00360-009-0346-4 | s2cid = 38796726 }} Cats are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome.{{cite journal | vauthors = Hiskett EK, Suwitheechon OU, Lindbloom-Hawley S, Boyle DL, Schermerhorn T | title = Lack of glucokinase regulatory protein expression may contribute to low glucokinase activity in feline liver | journal = Veterinary Research Communications | volume = 33 | issue = 3 | pages = 227–40 | date = March 2009 | pmid = 18780155 | doi = 10.1007/s11259-008-9171-6 | s2cid = 11115622 }}

Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetes (MODY2) or hyperinsulinemic hypoglycemia, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia.{{cite journal | vauthors = Arden C, Trainer A, de la Iglesia N, Scougall KT, Gloyn AL, Lange AJ, Shaw JA, Matschinsky FM, Agius L | title = Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic beta-cells: evidence for cellular instability of catalytic activity | journal = Diabetes | volume = 56 | issue = 7 | pages = 1773–82 | date = July 2007 | pmid = 17389332 | doi = 10.2337/db06-1151 | doi-access = free }}{{cite journal | vauthors = García-Herrero CM, Galán M, Vincent O, Flández B, Gargallo M, Delgado-Alvarez E, Blázquez E, Navas MA | title = Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity | journal = Diabetologia | volume = 50 | issue = 2 | pages = 325–33 | date = February 2007 | pmid = 17186219 | doi = 10.1007/s00125-006-0542-7 | doi-access = free }}{{cite journal | vauthors = Heredia VV, Carlson TJ, Garcia E, Sun S | title = Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations | journal = The Journal of Biological Chemistry | volume = 281 | issue = 52 | pages = 40201–7 | date = December 2006 | pmid = 17082186 | doi = 10.1074/jbc.M607987200 | doi-access = free }}{{cite journal | vauthors = Pino MF, Kim KA, Shelton KD, Lindner J, Odili S, Li C, Collins HW, Shiota M, Matschinsky FM, Magnuson MA | title = Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations | journal = The Journal of Biological Chemistry | volume = 282 | issue = 18 | pages = 13906–16 | date = May 2007 | pmid = 17353190 | doi = 10.1074/jbc.M610094200 | doi-access = free }}

The glucokinase of "knockout mice" who lack GKRP has a reduced expression and is entirely found in the cytoplasm. The knockout mice do not respond rapidly to glucose, exhibiting impaired glucose tolerance.{{cite journal | vauthors = Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM, Shiota C, Kaur S, Magnuson MA, Grippo JF | title = Characterization of glucokinase regulatory protein-deficient mice | journal = The Journal of Biological Chemistry | volume = 275 | issue = 11 | pages = 7826–31 | date = March 2000 | pmid = 10713097 | doi = 10.1074/jbc.275.11.7826 | doi-access = free }}

Mutations of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglycerides, C-reactive protein, and higher or lower risks for type 2 diabetes mellitus.{{cite journal | vauthors = Køster B, Fenger M, Poulsen P, Vaag A, Bentzen J | title = Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population | journal = Diabetic Medicine | volume = 22 | issue = 12 | pages = 1677–82 | date = December 2005 | pmid = 16401311 | doi = 10.1111/j.1464-5491.2005.01700.x | s2cid = 20786263 | doi-access = free }}{{cite journal | vauthors = Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C, Tewhey R, Rieder MJ, Hall J, Abecasis G, Tai ES, Welch C, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker PI, Burtt N, Voight BF, Hirschhorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson KF, Taskinen MR, Wahlstrand B, Hughes TE, Parnell LD, Lai CQ, Berglund G, Peltonen L, Vartiainen E, Jousilahti P, Havulinna AS, Salomaa V, Nilsson P, Groop L, Altshuler D, Ordovas JM, Kathiresan S | display-authors = 6 | title = Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations | journal = Diabetes | volume = 57 | issue = 11 | pages = 3112–21 | date = November 2008 | pmid = 18678614 | pmc = 2570409 | doi = 10.2337/db08-0516 }}{{cite journal | vauthors = Tam CH, Ma RC, So WY, Wang Y, Lam VK, Germer S, Martin M, Chan JC, Ng MC | title = Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents | journal = Diabetes | volume = 58 | issue = 3 | pages = 765–9 | date = March 2009 | pmid = 19073768 | pmc = 2646078 | doi = 10.2337/db08-1277 }}{{cite journal | vauthors = Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Köttgen A | title = Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study | journal = PLOS ONE | volume = 5 | issue = 7 | pages = e11690 | date = July 2010 | pmid = 20661421 | pmc = 2908550 | doi = 10.1371/journal.pone.0011690 | bibcode = 2010PLoSO...511690B | doi-access = free }}

Activators of GK are being investigated as possible medicines for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP.{{cite journal | vauthors = Futamura M, Hosaka H, Kadotani A, Shimazaki H, Sasaki K, Ohyama S, Nishimura T, Eiki J, Nagata Y | title = An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism | journal = The Journal of Biological Chemistry | volume = 281 | issue = 49 | pages = 37668–74 | date = December 2006 | pmid = 17028192 | doi = 10.1074/jbc.M605186200 | doi-access = free }}

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Category:Proteins