Sequence-based identification of amyloidogenic -hairpins reveals a prostatic acid phosphatase fragment promoting semen amyloid formation.
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abstract
-Structure-rich amyloid fibrils are hallmarks of several diseases, including Alzheimer's (AD), Parkinson's (PD), and type 2 diabetes (T2D). While amyloid fibrils typically consist of parallel -sheets, the anti-parallel -hairpin is a structural motif accessible to amyloidogenic proteins in their monomeric and oligomeric states. Here, to investigate implications of -hairpins in amyloid formation, potential -hairpin-forming amyloidogenic segments in the human proteome were predicted based on sequence similarity with -hairpins previously observed in A, -synuclein, and islet amyloid polypeptide, amyloidogenic proteins associated with AD, PD, and T2D, respectively. These three -hairpins, established upon binding to the engineered binding protein -wrapin AS10, are characterized by proximity of two sequence segments rich in hydrophobic and aromatic amino acids, with high -aggregation scores according to the TANGO algorithm. Using these criteria, 2505 potential -hairpin-forming amyloidogenic segments in 2098 human proteins were identified. Characterization of a test set of eight protein segments showed that seven assembled into Thioflavin T-positive aggregates and four formed -hairpins in complex with AS10 according to NMR. One of those is a segment of prostatic acid phosphatase (PAP) comprising amino acids 185-208. PAP is naturally cleaved into fragments, including PAP(248-286) which forms functional amyloid in semen. We find that PAP(185-208) strongly decreases the protein concentrations required for fibril formation of PAP(248-286) and of another semen amyloid peptide, SEM1(86-107), indicating that it promotes nucleation of semen amyloids. In conclusion, -hairpin-forming amyloidogenic protein segments could be identified in the human proteome with potential roles in functional or disease-related amyloid formation.
