Stability and inter-domain interactions modulate amyloid binding activity of a General Amyloid Interaction Motif.

08:00 EDT 27th March 2019 | BioPortfolio

Summary of "Stability and inter-domain interactions modulate amyloid binding activity of a General Amyloid Interaction Motif."

The M13 tip protein, g3p, binds the C-terminal domain of the bacterial membrane protein TolA via β-sheet augmentation, facilitating viral entry into E. coli. G3p binding leads to rearrangement of the β strands and partial unfolding of TolA. G3p also binds multiple amyloid assemblies with high affinity, and it can remodel them into amorphous aggregates. We previously showed that amyloid binding activity is defined by the two g3p N-terminal domains, which we call the General Amyloid Interaction Motif (GAIM). GAIM-hIgG1Fc fusions, which add immune effector function to amyloid targeting of GAIM, mediate reduction of two CNS amyloid deposits, Aβ plaques and tau tangles, in transgenic animal models of neurodegenerative disease. We carried out site-directed mutagenesis of GAIM to identify variants with altered amyloid binding and remodeling activity. A small set of residues along the inner strands of the two domains regulates both activities. The specificity of amyloid binding is governed by individual domain stability and inter-domain interactions. Our studies reveal several lines of similarity between GAIM binding to amyloids and g3p binding to its E. coli membrane target, TolA. Based on these studies, we designed new GAIM fusions which show enhanced binding potency towards multiple amyloid aggregates.


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This article was published in the following journal.

Name: Journal of molecular biology
ISSN: 1089-8638


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