Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.
α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α(2)M with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α(2)M. This study investigates, the effect of activation on the ability of α(2)M to inhibit amyloid formation by Aβ(1-42) and I59T human lysozyme and shows that protease-activated α(2)M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway.
Illawarra Health & Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, Australia.
Amy R
AR
Wyatt
Patrick
P
Constantinescu
Heath
H
Ecroyd
Christopher M
CM
Dobson
Mark R
MR
Wilson
Janet R
JR
Kumita
Justin J
JJ
Yerbury
D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry; D052160:Benzothiazoles; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009113:Muramidase / Q000737:chemistry / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D055503:Protein Multimerization; D013844:Thiazoles / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry*; D000511:alpha-Macroglobulins / Q000737:chemistry*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; D000511:alpha-Macroglobulins; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D009113:Muramidase; D014357:Trypsin