Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation.
American Association for the Advancement of Science (AAAS)
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West, J., Satapathy, S., Whiten, D. R., Kelly, M., Geraghty, N. J., Proctor, E., Sormanni, P., et al. (2021). Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation.. Sci Adv, 7 (50) https://doi.org/10.1126/sciadv.abf7606
Neuroserpin is a secreted protease inhibitor known to inhibit amyloid formation by the Alzheimer’s beta peptide (Aβ). To test whether this effect was constrained to Aβ, we used a range of in vitro assays to demonstrate that neuroserpin inhibits amyloid formation by several different proteins and protects against the associated cytotoxicity but, unlike other known chaperones, has a poor ability to inhibit amorphous protein aggregation. Collectively, these results suggest that neuroserpin has an unusual chaperone selectivity for intermediates on the amyloid-forming pathway. Bioinformatics analyses identified a highly conserved 14-residue region containing an α helix shared between neuroserpin and the thyroxine-transport protein transthyretin, and we subsequently demonstrated that transthyretin also preferentially inhibits amyloid formation. Last, we used rationally designed neuroserpin mutants to demonstrate a direct involvement of the conserved 14-mer region in its chaperone activity. Identification of this conserved region may prove useful in the future design of anti-amyloid reagents.
External DOI: https://doi.org/10.1126/sciadv.abf7606
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333115
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Licence URL: https://creativecommons.org/licenses/by-nc/4.0/