Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/8341
Title: Mutations of evolutionarily conserved aromatic residues suggest that misfolding of the mouse prion protein may commence in multiple ways
Authors: PAL, SUMAN
UDGAONKAR, JAYANT B.
Dept. of Biology
Keywords: Aromatic residues
Hydrogen-exchange
Mass-spectrometry
Mouse prion protein
Partially unfolded form
prion misfolding
2023-DEC-WEEK1
TOC-DEC-2023
2023
Issue Date: Dec-2023
Publisher: Wiley
Citation: Journal of Neurochemistry, 167(05), 696-710.
Abstract: The misfolding of the mammalian prion protein from its α-helix rich cellular isoform to its β-sheet rich infectious isoform is associated with several neurodegenerative diseases. The determination of the structural mechanism by which misfolding commences, still remains an unsolved problem. In the current study, native-state hydrogen exchange coupled with mass spectrometry has revealed that the N state of the mouse prion protein (moPrP) at pH 4 is in dynamic equilibrium with multiple partially unfolded forms (PUFs) capable of initiating misfolding. Mutation of three evolutionarily conserved aromatic residues, Tyr168, Phe174, and Tyr217 present at the interface of the β2-α2 loop and the C-terminal end of α3 in the structured C-terminal domain of moPrP significantly destabilize the native state (N) of the protein. They also reduce the free energy differences between the N state and two PUFs identified as PUF1 and PUF2**. It is shown that PUF2** in which the β2-α2 loop and the C-terminal end of α3 are disordered, has the same stability as the previously identified PUF2*, but to have a very different structure. Misfolding can commence from both PUF1 and PUF2**, as it can from PUF2*. Hence, misfolding can commence and proceed in multiple ways from structurally distinct precursor conformations. The increased extents to which PUF1 and PUF2** are populated at equilibrium in the case of the mutant variants, greatly accelerate their misfolding. The results suggest that the three aromatic residues may have been evolutionarily selected to impede the misfolding of moPrP.
URI: https://doi.org/10.1111/jnc.16007
http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/8341
ISSN: 0022-3042
1471-4159
Appears in Collections:JOURNAL ARTICLES

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.