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Autocatalytic processes in cooperative mechanisms of prion diseases
Author(s) -
Laurent Michel
Publication year - 1997
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(97)00310-4
Subject(s) - cooperativity , autocatalysis , gene isoform , chemistry , conformational change , biophysics , kinetics , prion protein , bistability , autocatalytic reaction , protein folding , protein structure , catalysis , biochemistry , biology , physics , statistical physics , medicine , disease , pathology , quantum mechanics , gene
According to the leading theory, the agent responsible for prion diseases would be the conformational isomer PrP Sc of a cellular protein PrP C , the pathogenic form PrP Sc multiplying by converting the normal protein into a likeness of itself. The pathogenic isoform could catalyze the conformational transition so that the process, taken as a whole, is autocatalytic. However, in this simple but atypic model, unrealistic values of rate parameters are needed in order to account for the kinetics of the propagation of prion diseases. In this paper, I show that these limits can be overcome by assuming that catalysis proceeds through a multimeric assembly of the pathogenic isoform of the prion protein. Such a structure would indeed be able to provide cooperativity both at the assembly and conformational change levels, strongly reinforcing the autocatalytic character of the activated process. Moreover, such a property is a prerequisite to endow the metabolic system with dynamic bistability. Together with a good agreement regarding experimental data, this analysis is closely akin to Griffith's original idea concerning the thermodynamic conditions required for autocatalyzed modifications of any protein.