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The sweet side of RNA regulation: glyceraldehyde‐3‐phosphate dehydrogenase as a noncanonical RNA‐binding protein

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The glycolytic protein, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), has a vast array of extraglycolytic cellular functions, including interactions with nucleic acids. GAPDH has been implicated in the translocation of transfer RNA (tRNA), the regulation of cellular messenger RNA (mRNA) stability and translation, as well as the regulation of replication and gene expression of many single‐stranded RNA viruses. A growing body of evidence supports GAPDH–RNA interactions serving as part of a larger coordination between intermediary metabolism and RNA biogenesis. Despite the established role of GAPDH in nucleic acid regulation, it is still unclear how and where GAPDH binds to its RNA targets, highlighted by the absence of any conserved RNA‐binding sequences. This review will summarize our current understanding of GAPDH‐mediated regulation of RNA function. WIREs RNA 2016, 7:53–70. doi: 10.1002/wrna.1315 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), metabolism, and RNA binding. Schematic for the proposed links between GAPDH, metabolism, glucose sensing, and RNA binding. Under normal glucose conditions, GAPDH is involved in glycolysis. IKKβ mediates tumor necrosis factor‐α (TNFα)‐dependent inhibition of the tuberous sclerosis complex (TSC1‐TSC2) via phosphorylation, decreases its activity toward the G‐protein Rheb (Ras homolog enriched in the brain), and activates the mTOR (mammalian target of rapamycin) complex 1 (mTORc1), which leads to protein synthesis and cell growth. Under low glucose conditions, GAPDH is involved in several pathways. First, GAPDH may stabilize the glucose transporter (GLUT‐1) mRNA via binding to its AU‐rich 3′ UTR. Second, GAPDH binds to the 3′ UTR of interferon‐γ (IFN‐γ) and interleukin‐2 (IL‐2) and decreases translation of both cytokines, preventing activated T cells to reach full effector status. Third, GAPDH sequesters Rheb and prevents mTORc1 activation. Finally, in ketogenic diets, GAPDH may be free from glycolysis and able to destabilize the SCN1A mRNA to reduce translation of the sodium transporter NaV 1.1, and alleviate conditions linked to Dravet syndrome.
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Proposed RNA‐binding sites in glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). (a) Structure of the GAPDH monomer with the Rossman fold/NAD+‐binding domain (cyan) and the catalytic domain (blue). RNA was proposed to bind in or near the NAD+‐binding site. (b) Electrostatic potential of GAPDH mapped onto the solvent‐accessible surface and colored by electrostatic potential with electropositive regions colored blue and electronegative regions colored red. The positively charged substrate grooves span the entire length of the GAPDH tetramer along the P‐axis. (c) The dimer interface contains basic and aromatic residues that may play a role in RNA binding. Peptides that were proposed to be involved in RNA binding are highlighted in gray (peptide 252–260) and dark blue (residues 306–311).
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Interconnection between oligomeric interfaces and NAD+‐binding site. Dimer‐interface mutation T229K (cyan) induces a series of subtle conformational shifts that propagate throughout the glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) tetramer. We showed that regions displaying increased solvent exchange upon mutation (magenta) are clustered along the P axis: dimer and tetramer interfaces, and NAD+‐binding site (green sticks).
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Structural comparison of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and heterogeneous nuclear ribonucleoprotein L. (a) Structural overlay of monomeric GAPDH and HnRNP L (blue). The x‐ray structures of HnRNP L and GAPDH are shown separately in (b) and (c) for clarity. (b) X‐ray structure of the first RNA recognition motif (RRM) domain of HnRNP L (PDB code 3R27) showing the canonical βαββαβ motif. (c) Structure of the GAPDH monomer (PDB code 4WNC) showing the conserved structural motif (β′α′β′β′α′β′) in the catalytic domain. The NAD+‐binding domain of GAPDH is shown in white, the catalytic domain is shown in yellow and orange (RRM‐like subdomain).
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Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) structural overview. (a) Each GAPDH subunit is comprised of two domains, the Rossman fold/cofactor‐binding domain (cyan) and the catalytic domain (blue). (b) Tetrameric assembly of GAPDH (PDB code 4WNC). The four subunits (O‐R) are related to one another by three twofold symmetry axes (P, Q, and R). (c) The dimer interface is formed by antiparallel five‐stranded β‐sheets from the R and Q (or P and O) subunits.
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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