NR AIPI
AU Morrissey,M.P.; Shakhnovich,E.I.
TI Evidence for the role of PrPc helix 1 in the hydrophilic seeding of prion aggregates
QU Proceedings of the National Academy of Sciences of the United States of America 1999 Sep 28; 96(20): 11293-8
PT journal article
AB Prions are mammalian proteins (PrPs) with a unique pathogenic property: a nonendogenous isoform PrPsc can catalyze conversion of the endogenous PrPc isoform into additional PrPsc. In this work, we demonstrate that PrPc helix 1 has certain properties (hydrophilicity, charge distribution) that make it unique among all naturally occurring alpha-helices, and which are indicative of a highly specific model of prion infectivity. The beta-nucleation model proposes that PrPsc is an aggregate with a hydrophilic core, consisting of a beta-sheet-like arrangement of constituent helix 1 components. It is suggested by using structural arguments, and confirmed by using CHARMM energy calculations, that aggregate formation from two PrPc molecules is highly unfavorable, but the addition of chains to an existing aggregate is favorable. The beta-nucleation model is shown to be consistent with the prion species-barrier, as well as with infectivity data. Sequence analysis of all known protein structures indicates that PrP is uniquely suited to beta-nucleation, in contrast to the many proteins that readily form less favorable (often nonspecific) hydrophobic aggregates.
MH Creutzfeldt-Jakob Syndrome/genetics; Human; Models, Molecular; Mutation; PrPc Proteins/*chemistry; *Protein Structure, Secondary; Support, U.S. Gov't, P.H.S.
AD Division of Engineering, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
SP englisch
PO USA