tailieunhanh - Báo cáo khoa học: The elusive intermediate on the folding pathway of the prion protein

A key molecular event in prion diseases is the conversion of the cellular conformation of the prion protein (PrP C ) to an altered disease-associated form, generally denoted as scrapie isoform (PrP Sc ). The molecular details of this conformational transition are not fully understood, but it has been suggested that an intermediate on the folding pathway of PrP C may be recruited to form PrP Sc . | ỊFEBS Journal The elusive intermediate on the folding pathway of the prion protein David C. Jenkins Ian D. Sylvester and Teresa J. T. Pinheiro Department of BiologicalSciences University of Warwick UK Keywords denaturant unfolding molten globule phasediagram prion conversion prion diseases Correspondence T. J. T. Pinheiro Department of Biological Sciences Gibbet Hill Road University of Warwick Coventry CV4 7AL UK Fax 44 2476 523 701 Tel 44 2476 528 364 E-mail Received 14 August 2007 revised 20 December 2007 accepted 15 January 2008 doi A key molecular event in prion diseases is the conversion of the cellular conformation of the prion protein PrPC to an altered disease-associated form generally denoted as scrapie isoform PrPSc . The molecular details of this conformational transition are not fully understood but it has been suggested that an intermediate on the folding pathway of PrPC may be recruited to form PrPSc. In order to investigate the folding pathway of PrP we designed and expressed two mutants each possessing a single strategically located tryptophan residue. The secondary structure and folding properties of the mutants were examined. Using conventional analyses of folding transition data determined by fluorescence and CD and novel phase-diagram analyses we present compelling evidence for the presence of an intermediate species on the folding pathway of PrP. The potential role of this intermediate in prion conversion is discussed. Prion diseases which include Creutzfeldt-Jakob disease in humans bovine spongiform encephalopathy in cattle and scrapie in sheep are associated with conversion of the normal cellular form of the prion protein PrPC to an altered pathological form generally designated as the scrapie isoform PrPSc . Such diseases can be sporadic inherited or acquired by transmission. Sporadic Creutzfeldt-Jakob disease accounts for 85 of all cases of the disease around 10-15 are associated .