Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 49, Pages 42777-42784Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.302539
Keywords
-
Categories
Funding
- National Institutes of Health [R01NS038604, R01NS044158, R01GM094357]
Ask authors/readers for more resources
The C-terminally-truncated human prion protein variant Y145Stop (or PrP23-144), associated with a familial prion disease, provides a valuable model for studying the fundamental properties of protein amyloids. In previous solid-state NMR experiments, we established that the beta-sheet core of the PrP23-144 amyloid is composed of two beta-strand regions encompassing residues similar to 113-125 and similar to 130-140. The former segment contains a highly conserved hydrophobic palindrome sequence, (113)AGAAAAGA(120), which has been considered essential to PrP conformational conversion. Here, we examine the role of this segment in fibrillization of PrP23-144 using a deletion variant, Delta 113-120 PrP23-144, in which the palindrome sequence is missing. Surprisingly, we find that deletion of the palindrome sequence affects neither the amyloidogenicity nor the polymerization kinetics of PrP23-144, although it does alter amyloid conformation and morphology. Using two-dimensional and three-dimensional solid-state NMR methods, we find that Delta 113-120 PrP23-144 fibrils contain an altered beta-core extended N-terminally to residue similar to 106, encompassing residues not present in the core of wild-type PrP23-144 fibrils. The C-terminal beta-strand of the core, however, is similar in both fibril types. Collectively, these data indicate that amyloid cores of PrP23-144 variants contain essential (i.e. nucleation-determining) and nonessential regions, with the latter being movable in amino acid sequence space. These findings reveal an intriguing new mechanism for structural polymorphism in amyloids and suggest a potential means for modulating the physicochemical properties of amyloid fibrils without compromising their polymerization characteristics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available