Molecular recycling within amyloid fibrils.
Amyloid fibrils are thread-like protein aggregates with a core region formed from repetitive arrays of beta-sheets oriented parallel to the fibril axis. Such structures were first recognized in clinical disorders, but more recently have also been linked to a variety of non-pathogenic phenomena ranging from the transfer of genetic information to synaptic changes associated with memory. The observation that many proteins can convert into similar structures in vitro has suggested that this ability is a generic feature of polypeptide chains. Here we have probed the nature of the amyloid structure by monitoring hydrogen/deuterium exchange in fibrils formed from an SH3 domain using a combination of nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. The results reveal that under the conditions used in this study, exchange is dominated by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. This insight into the dynamic nature of amyloid fibrils, and the ability to determine the parameters that define this behaviour, have important implications for the design of therapeutic strategies directed against amyloid disease.
Carulla
Natàlia
N
University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
Caddy
Gemma L
GL
Hall
Damien R
DR
Zurdo
Jesús
J
Gairí
Margarida
M
Feliz
Miguel
M
Giralt
Ernest
E
Robinson
Carol V
CV
Dobson
Christopher M
CM
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002417:Cattle; D041961:Deuterium Exchange Measurement; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D018909:src Homology Domains
D000682:Amyloid; D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases