PrP charge structure encodes interdomain interactions

Scientific Reports
Javier MartínezMaría Gasset

Abstract

Almost all proteins contain charged residues, and their chain distribution is tailored to fulfill essential ionic interactions for folding, binding and catalysis. Among proteins, the hinged two-domain chain of the cellular prion protein (PrP(C)) exhibits a peculiar charge structure with unclear consequences in its structural malleability. To decipher the charge design role, we generated charge-reverted mutants for each domain and analyzed their effect on conformational and metabolic features. We found that charges contain the information for interdomain interactions. Use of dynamic light scattering and thermal denaturation experiments delineates the compaction of the α-fold by an electrostatic compensation between the polybasic 23-30 region and the α3 electronegative surface. This interaction increases stability and disfavors fibrillation. Independently of this structural effect, the N-terminal electropositive clusters regulate the α-cleavage efficiency. In the fibrillar state, use of circular dichroism, atomic-force and fluorescence microscopies reveal that the N-terminal positive clusters and the α3 electronegative surface dictate the secondary structure, the assembly hierarchy and the growth length of the fibril state. These...Continue Reading

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Citations

Sep 7, 2016·Scientific Reports·Rosa SánchezMaría Gasset
Mar 16, 2016·Scientific Reports·Tania MassignanEmiliano Biasini
Mar 21, 2018·Biomolecules·Milagros CastellanosMaría Gasset
Jan 18, 2018·Journal of Neurochemistry·Michele Christine LandembergerVilma Regina Martins
Feb 28, 2019·Scientific Reports·Joan TorrentHuman Rezaei
Nov 3, 2016·The Biochemical Journal·Ankit SrivastavaBishwajit Kundu
May 10, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Graham P RosemanGlenn L Millhauser
Oct 18, 2020·Nucleic Acids Research·Alexandra LoukaAnnalisa Pastore

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Methods Mentioned

BETA
dynamic light scattering
NMR
AFM
transfections

Software Mentioned

WCIF ImageJ

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