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Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.

ABSTRACT: ?(2)-Macroglobulin (?(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of ?(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 ?(2)M. This study investigates, the effect of activation on the ability of ?(2)M to inhibit amyloid formation by A?(1-42) and I59T human lysozyme and shows that protease-activated ?(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.

SUBMITTER: Wyatt AR

PROVIDER: S-EPMC3581772 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.

Wyatt Amy R AR Constantinescu Patrick P Ecroyd Heath H Dobson Christopher M CM Wilson Mark R MR Kumita Janet R JR Yerbury Justin J JJ

FEBS letters 20130123 5

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 disti ...[more]

PMID: 23353684

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