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Séminaire Chimie IBMM

Post-transcriptional regulation of tumor necrosis factor (TNF)-α expression by the non-canonical RNA-binding protein glyceraldehyde-3-phosphate dehydrogenase

Dr. Elsa D. Garcin, Associate Professor (Department of Chemistry and Biochemistry, University of Maryland Baltimore County, USA)

publié le , mis à jour le

Le Mardi 12 Juillet 2016 à 10h30
UM Faculté de Pharmacie, amphithéâtre D
(attention, changement de date et de lieu)

(la conférence sera présentée en français)

The glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), possesses a vast array of extra-glycolytic functions, including regulation of protein expression via RNA binding. Despite the lack of a canonical RNA-binding motif, GAPDH binds to numerous adenine-uridine rich elements (AREs) from various mRNA 3’-untranslated regions in vitro and in vivo. How GAPDH binds to these AREs is still unknown. We discovered that GAPDH binds, in vitro, with high affinity to the core ARE from tumor necrosis factor-α (TNF-α) mRNA via a two-step binding mechanism. We investigated the effect of a dimer-interface mutation on GAPDH oligomerization and RNA binding by fluorescence anisotropy, crystallography, small-angle X-ray scattering, nano-electrospray ionization native mass spectrometry, and hydrogen-deuterium exchange mass spectrometry. We showed that the mutation promotes short-range and long-range dynamic changes in regions located at the dimer and tetramer interface and in the NAD+ binding site, suggesting that these regions are crucial for RNA binding. In addition, we have recently showed that GAPDH binds to and regulates the stability of TNF-α-mRNA in cells. We are currently combining NMR, crystallography, and hydrogen-deuterium exchange mass spectrometry to elucidate the RNA binding site in GAPDH, and provide structural information that will facilitate the design of novel therapeutic agents to treat TNF-α-associated diseases.

Contact local IBMM : Dr. May Morris, D.R. CNRS (DAPP).


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