Premium
Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils
Author(s) -
Honda Ryo,
Kuwata Kazuo
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701183rr
Subject(s) - nucleation , fibril , amyloid (mycology) , kinetics , biophysics , chemistry , helix (gastropod) , amyloid fibril , mutant , protein aggregation , crystallography , protein structure , biochemistry , amyloid β , biology , medicine , inorganic chemistry , ecology , physics , disease , organic chemistry , pathology , quantum mechanics , snail , gene
Amyloid fibrils are filamentous protein aggregates associated with the pathogenesis of a wide variety of human diseases. The formation of such aggregates typically follows nucleation‐dependent kinetics, wherein the assembly and structural conversion of amyloidogenic proteins into oligomeric aggregates (nuclei) is the ratelimiting step of the overall reaction. In this study, we sought to gain structural insights into the oligomeric nuclei of the human prion protein (PrP) by preparing a series of deletion mutants lacking 14–44 of the C‐terminal 107 residues of PrP and examined the kinetics and thermodynamics of these mutants in amyloid formation. An analysis of the experimental data using the concepts of the Ф‐value analysis indicated that the helix 2 region (residues 168–196) acquires an amyloid‐like β‐sheet during nucleation, whereas the other regions preserves a relatively disordered structure in the nuclei. This finding suggests that the helix 2 region serves as the nucleation site for the assemblyof amyloid fibrils.—Honda, R., Kuwata, K. Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils. FASEB J. 32, 3641–3652 (2018). www.fasebj.org