Salt-Mediated Oligomerization of the Mouse Prion Protein Monitored by Real-Time NMR

Journal of Molecular Biology
Ishita SenguptaJayant B Udgaonkar

Abstract

The prion protein forms β-rich soluble oligomers in vitro at pH4 in the presence of physiological concentrations of salt. In the absence of salt, oligomerization and misfolding do not take place in an experimentally tractable timescale. While it is well established that a lowering of pH facilitates misfolding and oligomerization of this protein, the role of salt remains poorly understood. Here, solution-state NMR was used to probe perturbations in the monomeric mouse prion protein structure immediately upon salt addition, prior to the commencement of the oligomerization reaction. The weak binding of salt at multiple sites dispersed all over the monomeric protein causes a weak and non-specific perturbation of structure throughout the protein. The only significant perturbation occurs in the loop between helix 2 and 3 in and around the partially buried K193-E195 salt bridge. The disruption of this key electrostatic interaction is the earliest detectable change in the monomer before any major conformational change occurs and appears to constitute the trigger for the commencement of misfolding and oligomerization. Subsequently, the kinetics of monomer loss, due to oligomerization, was monitored at the individual residue level. The o...Continue Reading

References

Nov 5, 1997·The Journal of Biological Chemistry·W SwietnickiW K Surewicz
Jun 19, 2007·The Journal of Physical Chemistry. B·Jennifer M Andrews, Christopher J Roberts

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Citations

May 24, 2018·Chemical Communications : Chem Comm·Ishita Sengupta, Jayant B Udgaonkar
May 13, 2018·Journal of Biomolecular NMR·João M C TeixeiraMiquel Pons
Sep 21, 2019·Biochemistry·Balaka Mondal, Govardhan Reddy
Sep 25, 2021·Protein Science : a Publication of the Protein Society·Suhas H BhateRanabir Das

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