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Metal-dependent amyloid β-degrading catalytic antibody construct

Paper ID Volume ID Publish Year Pages File Format Full-Text
23212 43420 2014 6 PDF Available
Title
Metal-dependent amyloid β-degrading catalytic antibody construct
Abstract

•Chelation of bound metal inhibited Aβ hydrolysis by a catalytic antibody fragment.•The metal accelerated a reaction step after initial antibody nucleophilic attack.•The hydrolytic but not chelator-inactivated antibody dissolved Aβ aggregates.•Zn-induced conformational transitions were associated with restored catalysis.•The antibody requires bound metal for efficient Aβ hydrolysis and dissolution.

Catalytic antibodies (catabodies) that degrade target antigens rapidly are rare. We describe the metal-dependence of catabody construct 2E6, an engineered heterodimer of immunoglobulin light chain variable domains that hydrolyzes amyloid β peptides (Aβ) specifically. In addition to the electrophilic phosphonate inhibitor of serine proteases, the metal chelators ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline completely inhibited the hydrolysis of Aβ by catabody 2E6. Formation of catabody-electrophilic phosphonate inhibitor adducts was unaffected by EDTA, suggesting that the metal exerts a favorable effect on a catalytic step after the initial catabody nucleophilic attack on Aβ. The EDTA inactivated catabody failed to disaggregate fibrillar Aβ, indicating the functional importance of the Aβ hydrolytic activity. Treating the EDTA-inactivated catabody with Zn2+ or Co2+ restored the Aβ hydrolytic activity, and Zn2+-induced catabody conformational transitions were evident by fluorescence emission spectroscopy. The studies reveal the absolute catabody dependence on a metal cofactor.

Keywords
AD, Alzheimer's disease; Aβ, amyloid β peptide; Aβ42, Aβ1-42; Aβ40, Aβ1-40; APP, Aβ precursor protein; BBB, blood–brain barrier; catabody, catalytic antibody; CDR, complementarity determining region; CAA, cerebral amyloid angiopathy; CHAPS, 3-[(3-cholamid
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Biotechnology - Volume 180, 20 June 2014, Pages 17–22
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us