Structural Basis for Regulation of Human Glucokinase by Glucokinase Regulatory Protein

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2013 Aug 21

PMID 23957911

Citations 21

Authors

Tobias Beck

Brian G Miller

Affiliations

Soon will be listed here.

Abstract

Glucokinase (GCK) is responsible for maintaining glucose homeostasis in the human body. Dysfunction or misregulation of GCK causes hyperinsulinemia, hypertriglyceridemia, and type 2 diabetes. In the liver, GCK is regulated by interaction with the glucokinase regulatory protein (GKRP), a 68 kDa polypeptide that functions as a competitive inhibitor of glucose binding to GCK. Formation of the mammalian GCK-GKRP complex is stimulated by fructose 6-phosphate and antagonized by fructose 1-phosphate. Here we report the crystal structure of the mammalian GCK-GKRP complex in the presence of fructose 6-phosphate at a resolution of 3.50 Å. The interaction interface, which totals 2060 Å(2) of buried surface area, is characterized by a small number of polar contacts and substantial hydrophobic interactions. The structure of the complex reveals the molecular basis of disease states associated with impaired regulation of GCK by GKRP. It also offers insight into the modulation of complex stability by sugar phosphates. The atomic description of the mammalian GCK-GKRP complex provides a framework for the development of novel diabetes therapeutic agents that disrupt this critical macromolecular regulatory unit.

Citing Articles

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References

Pal P, Miller B . Activating mutations in the human glucokinase gene revealed by genetic selection. Biochemistry. 2009; 48(5):814-6. DOI: 10.1021/bi802142q. View

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

Mukhtar M, Payne V, Arden C, Harbottle A, Khan S, Lange A . 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; 294(3):R766-74. DOI: 10.1152/ajpregu.00593.2007. View

Vionnet N, Stoffel M, Takeda J, Yasuda K, Bell G, Zouali H . Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992; 356(6371):721-2. DOI: 10.1038/356721a0. View

Choi J, Seo M, Kyeong H, Kim E, Kim H . Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc Natl Acad Sci U S A. 2013; 110(25):10171-6. PMC: 3690866. DOI: 10.1073/pnas.1300457110. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Kabsch W . XDS. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):125-32. PMC: 2815665. DOI: 10.1107/S0907444909047337. View

Anderka O, Boyken J, Aschenbach U, Batzer A, Boscheinen O, Schmoll D . Biophysical characterization of the interaction between hepatic glucokinase and its regulatory protein: impact of physiological and pharmacological effectors. J Biol Chem. 2008; 283(46):31333-40. DOI: 10.1074/jbc.M805434200. View

Baltrusch S, Lenzen S, Okar D, Lange A, Tiedge M . Characterization of glucokinase-binding protein epitopes by a phage-displayed peptide library. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase as a novel interaction partner. J Biol Chem. 2001; 276(47):43915-23. DOI: 10.1074/jbc.M105470200. View

10.

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

11.

Beer N, Tribble N, McCulloch L, Roos C, Johnson P, Orho-Melander M . The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet. 2009; 18(21):4081-8. PMC: 2758140. DOI: 10.1093/hmg/ddp357. View

12.

Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y . Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure. 2004; 12(3):429-38. DOI: 10.1016/j.str.2004.02.005. View

13.

Karplus P, Diederichs K . Linking crystallographic model and data quality. Science. 2012; 336(6084):1030-3. PMC: 3457925. DOI: 10.1126/science.1218231. View

14.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

15.

Van Schaftingen E, Vandercammen A, Detheux M, Davies D . The regulatory protein of liver glucokinase. Adv Enzyme Regul. 1992; 32:133-48. DOI: 10.1016/0065-2571(92)90013-p. View

16.

Nicholls R, Long F, Murshudov G . Low-resolution refinement tools in REFMAC5. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):404-17. PMC: 3322599. DOI: 10.1107/S090744491105606X. View

17.

Grimsby J, Coffey J, Dvorozniak M, Magram J, Li G, Matschinsky F . Characterization of glucokinase regulatory protein-deficient mice. J Biol Chem. 2000; 275(11):7826-31. DOI: 10.1074/jbc.275.11.7826. View

18.

Larion M, Kopke Salinas R, Bruschweiler-Li L, Miller B, Bruschweiler R . Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase. PLoS Biol. 2012; 10(12):e1001452. PMC: 3525530. DOI: 10.1371/journal.pbio.1001452. View

19.

Murshudov G, Skubak P, Lebedev A, Pannu N, Steiner R, Nicholls R . REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):355-67. PMC: 3069751. DOI: 10.1107/S0907444911001314. View

20.

De La Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart J, Ferrer J . Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase. FEBS Lett. 1999; 456(2):332-8. DOI: 10.1016/s0014-5793(99)00971-0. View