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PrP charge structure encodes interdomain interactions
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DOI：10.1038/srep13623.png)
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摘要
En 中文
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 (PrPC) 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 alpha-fold by an electrostatic compensation between the polybasic 23-30 region and the alpha 3 electronegative surface. This interaction increases stability and disfavors fibrillation. Independently of this structural effect, the N-terminal electropositive clusters regulate the alpha-cleavage efficiency. In the fibrillar state, use of circular dichroism, atomic-force and fluorescence microscopies reveal that the N-terminal positive clusters and the alpha 3 electronegative surface dictate the secondary structure, the assembly hierarchy and the growth length of the fibril state. These findings show that the PrP charge structure functions as a code set up to ensure function and reduce pathogenic routes.
Keyword:
HUMAN PRION PROTEIN
SALT BRIDGES
FOLDING PATHWAY
ALPHA-CLEAVAGE
WILD-TYPE
AGGREGATION
STABILITY
BINDING
DISEASE
MUTANT
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期刊
IF:
3.9
论文数:
27.9W
被引数:
83.5W
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