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Conformational polymorphism of wild‐type and mutant prion proteins: Energy landscape analysis
Author(s) -
Levy Yaakov,
Becker Oren M.
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10095
Subject(s) - gene isoform , mutant , helix (gastropod) , wild type , energy landscape , prion protein , chemistry , mutation , protein stability , transition (genetics) , biology , biophysics , biochemistry , gene , medicine , ecology , disease , pathology , snail
Conformational transitions are thought to be the prime mechanism of prion diseases. In this study, the energy landscapes of a wild‐type prion protein (PrP) and the D178N and E200K mutant proteins were mapped, enabling the characterization of the normal isoforms (PrP C ) and partially unfolded isoforms (PrP PU ) of the three prion protein analogs. It was found that the three energy landscapes differ in three respects: (i) the relative stability of the PrP C and the PrP PU states, (ii) the transition pathways from PrP C to PrP PU , and (iii) the relative stability of the three helices in the PrP C state. In particular, it was found that although helix 1 (residues 144‐156) is the most stable helix in wild‐type PrP, its stability is dramatically reduced by both mutations. This destabilization is due to changes in the charge distribution that affects the internal salt bridges responsible for the greater stability of this helix in wild‐type PrP. Although both mutations result in similar destabilization of helix 1, they a have different effect on the overall stability of PrP C and of PrP PU isoforms and on structural properties. The destabilization of helix 1 by mutations provides additional evidences to the role of this helix in the pathogenic transition from the PrP C to the pathogenic isoform PrP SC . Proteins 2002;47:458–468. © 2002 Wiley‐Liss, Inc.