Skip to main content
SpringerLink
Log in

The role of posttranslational modification in moonlighting glyceraldehyde-3-phosphate dehydrogenase structure and function

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a moonlighting protein exhibiting distinct activities apart from its classical role in glycolysis. Regulation of its moonlighting functions and its subcellular localization may be dependent on its posttranslational modification (PTM). The latter include its phosphorylation, which is required for its role in intermembrane trafficking, synaptic transmission and cancer survival; nitrosylation, which is required for its function in apoptosis, heme metabolism and the immune response; acetylation which is necessary for its modulation of apoptotic gene regulation; and N-acetylglucosamine modification which may induce changes in GAPDH oligomeric structure. These findings suggest a structure function relationship between GAPDH posttranslational modification and its diverse moonlighting activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Albakri Q, Stuehr D (1996) Intracellular assembly of inducible NO synthase is limited by nitric oxide-mediated changes in heme insertion and availability. J Biol Chem 271:5414–5421

    Article  CAS  PubMed  Google Scholar 

  • Azam S, Jouvet N, Jilani A et al (2008) Human glyceraldehyde-3-phosphate dehydrogenase plays a direct role in reactivating oxidized forms of the DNA repair enzyme APE1. J Biol Chem 283:30632–30641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Backlund M, Paukku K, Daviet L et al (2009) Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde-3-phosphate dehydrogenase. Nucl Acids Res 37:2346–2358

    Article  CAS  PubMed  Google Scholar 

  • Bonafe N, Gilmore-Hebert M, Folk N et al (2005) Glyceraldehyde-3-phosphate dehydrogenase binds to the AU-rich 3′ untranslated region of colony-stimulating factor-1 (CSF-1) messenger RNA in human ovarian cancer cells: possible role of CSF-1 posttranscriptional regulation and tumor phenotype. Cancer Res 65:3762–3771

    Article  CAS  PubMed  Google Scholar 

  • Brown V, Krynetski E, Krynetskaia N et al (2004) A novel CRM1-mediated nuclear export signal governs nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase following genotoxic stress. J Biol Chem 279:5984–5992

    Article  CAS  PubMed  Google Scholar 

  • Bruns G, Gerald P (1976) Human glyceraldehyde-3-phosphate dehydrogenase in man rodent somatic cell hybrids. Science 192:54–56

    Article  CAS  PubMed  Google Scholar 

  • Bruns G, Lalley P, Francke U, Minna J (1979) Gene mapping of the mouse by somatic cell hybridization. Cytogenet Cell Genet 25:139

    Google Scholar 

  • Chakravarti R, Aulak K, Fox P, Stueher D (2010) GAPDH regulates cellular heme insertion into inducible nitric oxide synthetase. Proc Nat’l Acad Sci, USA 104:18004–18009

    Article  Google Scholar 

  • Cho J, Lee R, Kim E et al (2018) PRMT1 negatively regulates activation-induced cell death in macrophages by arginine methylation of GAPDH. Exp Cell Res 368:50–58

    Article  PubMed  Google Scholar 

  • Demarse N, Ponnusamy S, Spicer E et al (2009) Direct binding of glyceraldehyde-3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. J Mol Bio 394:789–803

    Article  CAS  Google Scholar 

  • Glaser P, Gross R (1995) Rapid plasmenylethanolamine-selective fusion of membrane bilayers catalyzed by an isoform of glyceraldehyde-3 phosphate dehydrogenase: Discrimination between glycolytic and fusogenic roles of individual isoforms. Biochemistry 34:12194–12203

    Article  Google Scholar 

  • Hannibal L, Collins D, Brassard J et al (2012) Heme binding properties of glyceraldehyde-3-phosphate dehydrogenase. Biochemistry 51:8514–8529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hara M, Agrawal N, Kim S et al (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674

    Article  CAS  PubMed  Google Scholar 

  • Harada N, Yasunaga R, Higashimura Y et al (2007) Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells. J Biol Chem 282:22651–22661

    Article  CAS  PubMed  Google Scholar 

  • Huang Q, Lan F, Zheng Z et al (2011) Akt2 kinase suppresses glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-mediated apoptosis in ovarian cancer cells via phosphorylating GAPDH at threonine237 and decreasing its nuclear translocation. J Biol Chem 286:42211–42220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda Y, Yamaji R, Irie K, Kioka N, Murakami A (2012) Glyceraldehyde-3-phosphate dehydrogenase regulates cyclooxygenase-2 expression by targeting mRNA stability. Arch Biochem Biophys 528:141–147

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto R, Caswell A (1986) Autophosphorylation of glyceraldehyde-3-phosphate dehydrogenase and phosphorylation of protein from skeletal muscle microsomes. Biochemistry 11:657–661

    Google Scholar 

  • Kondo S, Kubota S, Mukudai Y et al (2011) Binding of glyceraldehyde-3-phosphate dehydrogenase to the cis- acting element of structure-anchored repression in ccn2 mRNA. Biochem Biophys Res Comm 405:382–387

    Article  CAS  PubMed  Google Scholar 

  • Kornberg M, Sen N, Hara M et al (2010) GAPDH mediates nitrosylation of nuclear proteins. Nat Cell Biol 12:1094–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar S, Sheokand N, Mhadeshwar M et al (2012) Characterization of glyceraldehyde-3-phosphate dehydrogenase as a novel transferrin receptor. Int J Biochem Cell Biol 44:189–199

    Article  CAS  PubMed  Google Scholar 

  • Laschet J, Minier F, Kurcewicz I et al (2004) Glyceraldehyde-3-phosophate dehydrogenase is a GABAA receptor kinase linking glycolysis to neuronal inhibition. J Neurosci 24:7614–7622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lazarov V, Guzhova I, Margulis B (2020) Glyceraldehyde-3-phosphate dehydrogenase is a multifaceted therapeutic target. Pharmaceutics 12:416–432

    Article  Google Scholar 

  • Lee S, Kim C, Lee K-H, Ahn J-Y (2012) S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1-GAPDH death cascade. J Cell Biol 199:65–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer-Siegler K, Mauro D, Seal G et al (1991) A human nuclear uracil DNA glycosylase is the 37 kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proc Nat’l Acad Sci USA 88:8460–8464

    Article  CAS  Google Scholar 

  • Mezquita J, Pau M, Mezquita C (1998) Several novel transcripts of glyceraldehyde- 3-phosphate dehydrogenase expressed in adult chicken testis. J Cell Biochem 71:127–139

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa T, Hirano Y, Inomata A (2002) Participation of a fusogenic protein. glyceraldehyde-3-phosphate dehydrogenase, in nuclear membrane assembly. J Biol Chem 278:20395–20404

    Article  Google Scholar 

  • Park J, Han D, Kim K, Kang Y, Kim Y (2009) O-GlcNAcylation disrupts glyceraldehyde-3-phosphate dehydrogenase homo-tetramer formation and mediates its nuclear translocation. Biochim Biophys Acta 1794:254–262

    Article  CAS  PubMed  Google Scholar 

  • Raje C, Kumar S, Harle A et al (2007) The macrophage cell surface glyceraldehyde-3-phosphate dehydrogenase is a novel transferrin receptor. J Biol Chem 282:3252–3261

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Pascual F, Redondo-Horcajo M, Magan-Marchal N et al (2008) Glyceraldehyde-3-phosphate dehydrogenase regulates endothelin-1 expression by a novel, redox-sensitive mechanism involving mRNA stability. Mol Cell Biol 28:7139–7155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen N, Hara M, Kornberg M et al (2008) Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nature Cell Biol 10:866–873

    Article  CAS  PubMed  Google Scholar 

  • Sen N, Hara M, Ahmad A et al (2009) GOSPEL, a neuroprotective protein that binds to GAPDH upon S-nitrosylation. Neuron 63:81–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sergienko E, Kharitonenkov A, Bulargina T et al (1992) D-glyceraldehyde-3-phosphate dehydrogenase purified from rabbit muscle contains phosphotyrosine. FEBS Lett 304:21–23

    Article  CAS  PubMed  Google Scholar 

  • Sheokand N, Kumar S, Malhotra H et al (2013) Secreted glyceraldehyde-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition. Biochim Biophys Acta 1830:3818–3827

    Google Scholar 

  • Sirover M (1999) New insight into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1432:159–184

    Article  CAS  PubMed  Google Scholar 

  • Sirover M (2005) New nuclear functions of the glycolytic protein glyceraldehyde-3- phosphate dehydrogenase. J Cell Biochem 95:45–52

    Article  CAS  PubMed  Google Scholar 

  • Sirover M (2011) On the functional diversity of glyceraldehyde-3- phosphate dehydrogenase: biochemical mechanisms and regulatory control. Biochim Biophys Acta 1810:741–751

    Article  CAS  PubMed  Google Scholar 

  • Sirover M (2012) Subcellular dynamics of multifunctional protein regulation: mechanisms of GAPDH intracellular translocation. J Cell Biochem 113:2193–2200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sirover M (2014) Structural analysis of glyceraldehyde-3- phosphate dehydrogenase functional diversity. Int’l J Biochem Cell Biol 57:20–26

    Article  CAS  Google Scholar 

  • Sirover M (2017) Glyceraldehyde-3- phosphate dehydrogenase (GAPDH): the quintessential moonlighting protein in normal cell function and in human disease. Elsevier, London United Kingdom

    Google Scholar 

  • Sweeney E, Singh A, Chakravarti R et al (2018) Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J Biol Chem 293:14557–14568

    Article  Google Scholar 

  • Tisdale E (1999) A Rab2 mutant with impaired GTPase activity stimulates vesicle formation from pre-Golgi intermediates. Mol Biol Cell 10:1837–1849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tisdale E (2001) Glyceraldehyde-3-phosphate dehydrogenase is required for vesicular transport in the early secretory pathway. J Biol Chem 276:2480–2486

    Article  CAS  PubMed  Google Scholar 

  • Tisdale E (2002) Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Cί/λ and plays a role in microtubule dynamics in the early secretory pathway. J Biol Chem 277:3334–3341

    Article  CAS  PubMed  Google Scholar 

  • Tisdale E (2006) Artalejo C (2006) Src-dependent aprotein kinase Ci/l (aPKCi/l) tyrosine phosphorylation is required for aPKCi/l association with Rab2 and glyceraldehyde-3-phosphate dehydrogenase on pre-golgi intermediates. J Biol Chem 281:8436–8442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ventura M, Mateo F, Serratosa J et al (2010) Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int J Biochem Cell Biol 42:1672–1680

    Article  CAS  PubMed  Google Scholar 

  • Vollberg T, Cool B, Sirover M (1987) Biosynthesis of the human base excision repair enzyme uracil DNA glycosylase. Can Res 47:123–128

    CAS  Google Scholar 

  • Waheed D, Ghosh A, Chakravarti R et al (2010) Nitric oxide blocks cellular heme insertion into a broad range of heme proteins. Free Rad Biol Med 48:1548–1558

    Article  CAS  PubMed  Google Scholar 

  • Zeng T, Dong Z-F, Liu S-J et al (2014) A novel variant in the 3′ UTR of human SCN1Agene from a patient with Dravel syndrome decreases mRNA stability mediated by GAPDH’s binding. Hum Genet 133:801–811

    Article  PubMed  Google Scholar 

  • Zheng I, Roeder R, Luo Y (2013) S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114:255–266

    Article  Google Scholar 

  • Zhou Y, Yi X, Stoffer J et al (2008) The multifunctional protein glyceraldehyde-3-phosphate dehydrogenase is both regulated and controls colony-stimulating factor-1 messenger RNA stability in ovarian cancer. Mol Can Res 6:1375–1380

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

    Michael A. Sirover

Authors
  1. Michael A. Sirover
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Sirover.

Ethics declarations

Conflict of interest

There are no conflicts of interest.

Additional information

Handling editor: D. Tsikas.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sirover, M.A. The role of posttranslational modification in moonlighting glyceraldehyde-3-phosphate dehydrogenase structure and function. Amino Acids 53, 507–515 (2021). https://doi.org/10.1007/s00726-021-02959-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-021-02959-z

Keywords

Search

Navigation