Proline conformation in intrinsically unfolded proteins : sense or nonsense?"

The conformational state of distinct prolines can determine the folding of a protein but equally other biological processes when coupled to a conformation sensitive secondary reaction. The importance of proline conformation is underscored by the interaction of many of those proteins with different prolyl cis/trans isomerases.

We will present our results on the proline conformation in two examples, the neuronal protein Tau and the non-structural protein NS5A of the HCV virus. For Tau, a number of molecular diseases including Alzheimer’s disease (AD) and Traumatic Brain injury (TBI) were recently qualified as “cistauois” (Kondo et al. 2015) and would imply a cis conformation for the pThr213-Pro232 prolyl bond. For NS5A, the molecular interaction between NS5A and the host cyclophilin is essential for the viral RNA replication, and implies a small motif centered on a particular proline residue (Dujardin et al., 2015).

Using NMR spectroscopy as an analytical tool, we have investigated the conformational aspects of the different prolines in both systems, and will discuss the possible interaction with prolyl cis/trans isomerases such as Pin1and FKBP52 (Giustiniani et al., PNAS 2014).

References

Dujardin et al., A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication. , J Biol Chem. 2015 Jul 31;290(31):19104-20.

Kondo et al., Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy., Nature. 2015 Jul 23;523(7561):431-6.

Giustiniani  et al., Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4584-9.