Folding pathways of prion and doppel.

Abstract:

:The relevance of various residue positions for the stability and the folding characteristics of the prion protein in its normal cellular form are investigated by using molecular dynamics simulations of models exploiting the topology of the native state. These models allow for reproducing the experimentally validated two-state behavior of the normal prion isoform. Highly significant correlations are found between the most topologically relevant sites in our analysis and the single point mutations known to be associated with the arousal of the genetic forms of prion disease. Insight into the conformational change is provided by comparing the folding process of cellular prion and doppel that share a similar native state topology: the folding pathways of the former can be grouped in two main classes according to which tertiary structure contacts are formed first enroute to the native state. For the latter a single class of pathways leads to the native state again through a two-state process. Our results are consistent and supportive of the recent experimental findings that doppel lacks the scrapie isoform and that such remarkably different behavior involves residues in the region containing the two beta-strands and the intervening helix.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Settanni G,Hoang TX,Micheletti C,Maritan A

doi

10.1016/S0006-3495(02)75353-8

subject

Has Abstract

pub_date

2002-12-01 00:00:00

pages

3533-41

issue

6

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(02)75353-8

journal_volume

83

pub_type

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