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Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation

Journal Article


Abstract


  • Neuroserpin is a secreted protease inhibitor known to inhibit amyloid formation by the Alzheimer���s beta peptide (A��). To test whether this effect was constrained to A��, 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 �� 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.

Publication Date


  • 2021

Citation


  • West, J., Satapathy, S., Whiten, D. R., Kelly, M., Geraghty, N. J., Proctor, E. J., . . . Wilson, M. R. (2021). Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation. Science Advances, 7(50). doi:10.1126/sciadv.abf7606

Scopus Eid


  • 2-s2.0-85116288208

Volume


  • 7

Issue


  • 50

Place Of Publication


Abstract


  • Neuroserpin is a secreted protease inhibitor known to inhibit amyloid formation by the Alzheimer���s beta peptide (A��). To test whether this effect was constrained to A��, 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 �� 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.

Publication Date


  • 2021

Citation


  • West, J., Satapathy, S., Whiten, D. R., Kelly, M., Geraghty, N. J., Proctor, E. J., . . . Wilson, M. R. (2021). Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation. Science Advances, 7(50). doi:10.1126/sciadv.abf7606

Scopus Eid


  • 2-s2.0-85116288208

Volume


  • 7

Issue


  • 50

Place Of Publication