PAP(248-286) Conformational Changes during the Lag Phase of Amyloid Fibril Formation

The initial stage of fibril formationof C-terminal region PAP(248-286)of human seminal plasma protein prostatic acid phosphatase was considered.Amyloid fibrils from the peptide PAP(248-286) are termed asa semen-derived enhancer of viral infection (SEVI) found in abundantquantities in semen. The kinetics of the amyloid fibril formationprocess consists of two characteristic phases (lag phase/nucleationphase and growth phase/elongation phase). The lag phase can be causedby the presence of mature amyloid fibrils (seeds) in protein solution,so-called secondary nucleation. The secondary nucleation includesinteraction of protein monomers with the mature fibril surface thatleads to protein spatial structural changes for further amyloid fibrilformation. In this work, changes of the PAP(248-286) spatialstructure were obtained during the secondary nucleation phase. Pulsed-fieldgradient (PFG) NMR was used to characterize the behavior of monomericPAP(248-286) in water solution after PAP(248-286) seedaddition. The self-diffusion coefficient showed compactization ofthe peptide monomer due to fibril-monomer interactions. PAP(248-286)spatial structural changes were detected with the help of high-resolutionNMR spectroscopy and molecular dynamics (MD) simulation. The foldingof PAP(248-286) occurs due to backbone chain bending in theregion of H270 and T275 amino acid residues. Obtained folded conformationof PAP(248-286) emerging in the secondary nucleation processis energetically favorable and retains after monomer-amyloidinteraction. The structural changes are associated with localizationof PAP(248-286) hydrophobic surface regions, which are probablyresponsible for peptide monomer-amyloid interactions.