Structure and dynamics of the ‘protein folding code’ infe(4)

图片特写：“争夺”图书馆 | 依法治校

R.Wallace/BioSystems103 (2011) 18–26

21

Fig.3.From Sawaya et al.(2007).The eight possible steric zipper symmetry classifications for amyloidfibrils.

Falsig et al.(2008)examine the many different strains of pri-ons,finding that differences in kinetics of the elementary steps of prion growth underlie the differential proliferation of prion strains,based on differential frangibility of prionfibrils.They argue that an important factor is the size of the stabilizing cross-␤amyloid core that appears to define the physical properties of the resulting structures,including their propensity to frag-ment,with small core sizes leading to enhanced frangibility. In terms of the protein folding funnel approach,theyfind that intrinsic frustration implies that several distinct arrangements favoring a certain subset of globally incompatible interactions are possible,reflecting the observed strain-dependent differ-ences in the parts of the sequence incorporated into thefibril core.

In addition,they argue,there are unexplored similarities between Alzheimer’s and prion diseases,that is,the analogies between prion and A␤aggregates could be broader than initially suspected.

Given the eightfold symmetry of the amyloidfiber,say versions A→H,then the simplest‘frangibility code’is the set of identical pairings:{AA,BB,...,GG,HH},producing eight different possible structures and their reproduction by fragmentation.More complex prion symmetries,or the possibility of combinatorial recombina-tion,would allow a much richer structure,producing quasi-species, in the sense of Collinge and Clarke(2007).Permitting different sequence lengths or explicitly identifying different sequence orders would vastly enlarge what Collinge has characterized as a‘cloud’of possibilities,in the case of prion diseases.Indeed,classic studies by Bruce and Dickinson(1987)found15or more different prion strains in a mouse model.

Recent work on prions appears to support something of Maury’s hypothesis.Li et al.(2010)find that infectious prions,mainly what