Kinase Family GAPDH

Kinase Classification: Group SAPPK: Family GAPDH

The glycolytic enzyme, Glyceraldehyde-3-phosphate dehydrogenase has been demonstrated to have a kinase activity towards viral proteins, a GABA receptor, and in vitro.

GAPDH and Glycolysis

GAPDH has a kinase function during glycolysis: it first oxidizes glyceraldehyde 3-phosphate, converting the aldehyde group to a carboxylic acid, and then adds inorganic phosphate to the alcohol group of that carboxylic acid (Wikipedia). GAPDH uses the energy from the first reaction to drive the unusual, and energetically unfavorable, phosphorylation with orthophosphate (Pi). The next step in glycolysis inovlves phosphoglycerate kinase (PGK) acting as a form of phosphatase or reverse kinase: it removes one of the phosphates on the glyceraldehyde diphosphate by converting ADP to ATP.

Evidence for Protein Kinase Activity

GAPDH from rabbit muscle was reported to autophosphorylate and transphosphorylate two uncharacterized proteins [1]. Transphosphorylation appeared to involve transfer of the phosphate originally used to autophosphorylate, using ATP as a donor. The pH lability profile of the autophosphorylated form suggested the presence of an acyl phosphate (probably phosphorylation of carboxylic acid) rather than the typical ester phosphates of Ser/Thr/Tyr phosphorylation.

GAPDH has been reported to phosphorylate GABRA1, a subunit of the receptor for the inhibitory neurotransmitter GABA [2]. GAPDH binds tightly to GABRA1, and phosphorylates it on T337 and S416, both residues found within a conserved Nxxx[S/T]K motif. Labeling experiments suggest that GAPDH and PGK produce ATP while anchored at the receptor, and that GAPDH uses this ATP to autophosphorylate and transphosphorylate the receptor. This system may have evolved from one where glycolytic enzymes are localized to the membrane to produce ATP to power ATPase-driven ion channels [3, 4], and suggests that the phosphorylation may be regulatory and may respond to levels of ATP/ADP/Pi, Mg++ or glycolytic precursors. A separate study [4] also reports GAPDH autophosphorylation at the neuronal post-synaptic density, and that autophosphorylated GAPDH had an increased affinity for binding actin.

GAPDH has also been reported to phosphorylate the core protein of hepatitis B virus [5].

Other Functions

GAPDH has also been reported to activate transcription, as part of the OCA-S complex, along with lactate dehydrogenase [6]; may link NO signaling to apoptosis [7]; and be involved in ER-to-Golgi transport [8]

GAPDH is also the substrate or binding partner of typical protein kinases, including PKC, CAMK2 and EGFR, Src, and has been reported to be tightly bound to nucleoside diphosphate kinases (NDK)

Domain Structure

GAPDH consists of a NADB_Rossman fold followed by a specific GAPDH domain.

Evolution

GAPDH is found in almost all organisms due to its role in glycolysis.

References

1. Kawamoto RM and Caswell AH. Autophosphorylation of glyceraldehydephosphate dehydrogenase and phosphorylation of protein from skeletal muscle microsomes. Biochemistry. 1986 Feb 11;25(3):657-61. DOI:10.1021/bi00351a022 |
2. Laschet JJ, Minier F, Kurcewicz I, Bureau MH, Trottier S, Jeanneteau F, Griffon N, Samyn B, Van Beeumen J, Louvel J, Sokoloff P, and Pumain R. Glyceraldehyde-3-phosphate dehydrogenase is a GABAA receptor kinase linking glycolysis to neuronal inhibition. J Neurosci. 2004 Sep 1;24(35):7614-22. DOI:10.1523/JNEUROSCI.0868-04.2004 |
3. Silver IA, Deas J, and Erecińska M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience. 1997 May;78(2):589-601. DOI:10.1016/s0306-4522(96)00600-8 |
4. Wu K, Aoki C, Elste A, Rogalski-Wilk AA, and Siekevitz P. The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endogenously generated nitric oxide. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13273-8. DOI:10.1073/pnas.94.24.13273 |
5. Duclos-Vallée JC, Capel F, Mabit H, and Petit MA. Phosphorylation of the hepatitis B virus core protein by glyceraldehyde-3-phosphate dehydrogenase protein kinase activity. J Gen Virol. 1998 Jul;79 ( Pt 7):1665-70. DOI:10.1099/0022-1317-79-7-1665 |
6. Zheng L, Roeder RG, and Luo Y. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell. 2003 Jul 25;114(2):255-66. DOI:10.1016/s0092-8674(03)00552-x |
7. Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, and Snyder SH. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3887-9. DOI:10.1073/pnas.0511321103 |
8. Tisdale EJ and Artalejo CR. A GAPDH mutant defective in Src-dependent tyrosine phosphorylation impedes Rab2-mediated events. Traffic. 2007 Jun;8(6):733-41. DOI:10.1111/j.1600-0854.2007.00569.x |