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Protein misfolding and aggregation: Insight from single molecule study
Author(s) -
Lyubchenko Yuri L,
Yu Junping,
Kim BoHyun
Publication year - 2009
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/fasebj.23.1_supplement.850.7
Subject(s) - force spectroscopy , chemistry , protein aggregation , biophysics , protein folding , neurodegeneration , folding (dsp implementation) , amyloid (mycology) , molecule , atomic force microscopy , nanotechnology , biochemistry , biology , materials science , medicine , inorganic chemistry , disease , organic chemistry , pathology , electrical engineering , engineering
Protein misfolding is the very fist step in a long chain of the aggregation events eventually leading to neurodegeneration. The structure of individual protein molecules within well ordered aggregates can be partially elucidated using established techniques, however, we still lack of a mechanistic understanding of the process leading to the misfolded conformations of a protein and their role in the aggregation. Our central hypothesis is that proteins in misfolded states are characterized by elevated interprotein interactions that can be detected by AFM force spectroscopy approach. We developed a novel nanoprobing AFM approach capable of detecting and analyzing transient misfolded states of the proteins differed from the normal ones by increased interprotein interactions. The proteins were immobilized covalently at the N or C termini at the AFM probes and substrates and their interactions were measured by multiple approach‐retractions cycles performed by the AFM instrument. These experiments applied to α‐synuclein and amyloid β‐peptide revealed enormously high stability of misfolded dimers suggesting their critical role in the early stages of the aggregates formation. A high stability of the misfolded dimers is unexpected finding that sheds a new light into the mechanisms of the self‐assembly of misfolded proteins into the disease related aggregates. Supported by DOE grant. DE‐FG02‐08ER64579.