Local environmental effects on the structure of the prion protein.
Prion diseases are neurodegenerative diseases causally linked to the partial unfolding and subsequent misfolding and aggregation of the prion protein (PrP). While most proteins fold into a single low energy state, PrP can fold into two distinct isoforms. In its innocuous state, denoted as PrPC, the protein has predominantly alpha-helical secondary structure, however, PrPC can misfold into an isoform rich in extended structure capable of forming toxic and infectious aggregates. While prion disease is believed to be a protein-only disease, one not requiring any non-protein elements for propagation, the different environments the protein finds itself in vivo likely influence its ability to misfold and aggregate. In this review we will examine various molecules, covalent modifications and environments PrP faces in vivo and the effect they have on PrP's local environment and, potentially, conformation. Included in this discussion are: (1) pH, (2) carbohydrates, (3) lipid membranes, (4) metal ions, and (5) small molecules.
DeMarco
Mari L
ML
Department of Medicinal Chemistry, Biomolecular Structure and Design Program, University of Washington, Seattle, WA 98195-7610, USA.
Daggett
Valerie
V
D000818:Animals; D001923:Brain Chemistry; D002241:Carbohydrates / Q000737:chemistry; D019295:Computational Biology; D004777:Environment; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008566:Membranes / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry
D002241:Carbohydrates; D011328:Prions; D011994:Recombinant Proteins