Structure-based optimization of a PDZ-binding motif within a viral peptide stimulates neurite outgrowth.

Protection of neuronal homeostasis is a major goal in the management of neurodegenerative diseases. Microtubule-associated Ser/Thr kinase 2 (MAST2) inhibits neurite outgrowth, and its inhibition therefore represents a potential therapeutic strategy. We previously reported that a viral protein (G-protein from rabies virus) capable of interfering with protein-protein interactions between the PDZ domain of MAST2 and the C-terminal moieties of its cellular partners counteracts MAST2-mediated suppression of neurite outgrowth.

Deciphering the unconventional peptide binding to the PDZ domain of MAST2.

Phosphatase and tensin homologue (PTEN) and microtubule-associated serine threonine kinase 2 (MAST2) are key negative regulators of survival pathways in neuronal cells. The two proteins interact via the PDZ (PSD-95, Dlg1, Zo-1) domain of MAST2 (MAST2-PDZ). During infection by rabies virus, the viral glycoprotein competes with PTEN for interaction with MAST2-PDZ and promotes neuronal survival.

Strategies to interfere with PDZ-mediated interactions in neurons: What we can learn from the rabies virus.

PDZ (PSD-95/Dlg/ZO-1) domains play a major role in neuronal homeostasis in which they act as scaffold domains regulating cellular trafficking, self-association and catalytic activity of essential proteins such as kinases and phosphatases. Because of their central role in cell signaling, cellular PDZ-containing proteins are preferential targets of viruses to hijack cellular function to their advantage. Here, we describe how the viral G protein of the rabies virus specifically targets the PDZ domain of neuronal enzymes during viral infection.

Ordered phosphorylation events in two independent cascades of the PTEN C-tail revealed by NMR.

PTEN phosphatase is a tumor suppressor controlling notably cell growth, proliferation and survival. The multisite phosphorylation of the PTEN C-terminal tail regulates PTEN activity and intracellular trafficking. The dynamical nature of such regulatory events represents a crucial dimension for timing cellular decisions.

Interference with the PTEN-MAST2 interaction by a viral protein leads to cellular relocalization of PTEN.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) and MAST2 (microtubule-associated serine and threonine kinase 2) interact with each other through the PDZ domain of MAST2 (MAST2-PDZ) and the carboxyl-terminal (C-terminal) PDZ domain-binding site (PDZ-BS) of PTEN. These two proteins function as negative regulators of cell survival pathways, and silencing of either one promotes neuronal survival. In human neuroblastoma cells infected with rabies virus (RABV), the C-terminal PDZ domain of the viral glycoprotein (G protein) can target MAST2-PDZ, and RABV infection triggers neuronal survival in a PDZ-BS-dependent fashion.

Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein.

The capacity of a rabies virus to promote neuronal survival (a signature of virulence) or death (a marker of attenuation) depends on the cellular partners recruited by the PDZ-binding site (PDZ-BS) of its envelope glycoprotein (G). Neuronal survival requires the selective association of the PDZ-BS of G with the PDZ domains of two closely related serine-threonine kinases, MAST1 and MAST2. Here, we found that a single amino acid change in the PDZ-BS triggered the apoptotic death of infected neurons and enabled G to interact with additional PDZ partners, in particular the tyrosine phosphatase PTPN4.

1H, 13C and 15N resonance assignments of the PDZ of microtubule-associated serine/threonine kinase 205 (MAST205) in complex with the C-terminal motif from the rabies virus glycoprotein.

Most of microbes hijack the cellular machinery to their advantage by interacting with specific target of the host cell. Glycoprotein of rabies virus is a key factor controlling the homeostasis of infected neuronal cells and proteins belonging to the human microtubule associated serine threonine kinase family have been identified as potential cellular partners. As a first step towards its structural study, we have assigned the backbone and side chain nuclei resonances of the PDZ domain (PSD-95, Discs Large, ZO-1) of MAST205 in complex with the C-terminal residues of the glycoprotein of rabies virus.