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Abstract
Background
Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs.
Objective
To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action.
Materials and Methods
We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods.
Results
We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids.
Conclusion
Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.
Acknowledgements
The authors thank Natalie Scheurmann (Ulm University) for technical assistance in protein purification and Nico Preising from the Core Facility Functional Peptidomics (Ulm University) for peptide synthesis.
Author contributions
T.M, I.P.-G., A.A.R. and L.S. carried out experiments. M.M., W.-G. F. and L.S. contributed reagents and materials. T.M, I.P.-G., C.H., J.B., A.R.-A., S.W., C.Q.S. and M.F. analysed data. M.F. designed research. T.M. and M.F. wrote the paper. All authors could comment on the manuscript.
Disclosure statement
W.-G.F. has business interests in Pharis Biotech GmbH that may be affected by the research reported in the enclosed paper. T.M., I.P.-G., C.H., J.B., A.R.-A., S.W., C.Q.S., M.M, L.S and M.F. have no potential conflict of interest to declare.