Multiple psychiatric disorders are linked to an imbalance in dopamine and glutamate synaptic transmission within the reward circuit. From mice to humans, we found that drug addiction and major depression are linked to an increased interaction between dopamine and glutamate receptors. Disrupting theses interactions mitigates addictive-like and depressive-like symptoms in preclinical models, therefore supporting that targeting these receptor heteromers may harbor translational potentials for future therapeutic developments.
Many of the replication factors that help replicate DNA act in concert in a dynamic protein complex referred to as the replisome. Using an integrative structural biology approach, combining NMR, X-ray crystallography and cryo-EM with DNA polymerization assays, our aim is to decipher the molecular mechanisms required for the assembly of the archaeal replisome, which is a distant and simpler relative of the eukaryotic one. Our latest work focused on the essential replisome component Replication Protein A (RPA), which plays a pivotal role in DNA replication, avidly coating exposed single-stranded DNA as soon as the double-helix is unwound. We unveiled how RPA uses a conserved C-terminal winged-helix domain to interact with two key actors of the replisome regulating their activity: the DNA primase (PriSL) and the replicative DNA polymerase (PolD). We present multiple structures explaining a conserved mechanism for RPA-mediated interactions, which shares its ancestor with eukaryotic RPA and the CST telomere maintenance complex.
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