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

Abstract

The initial stage of fibril formation of 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 as a semen-derived enhancer of viral infection (SEVI) found in abundant quantities in semen. The kinetics of the amyloid fibril formation process consists of two characteristic phases (lag phase/nucleation phase and growth phase/elongation phase). The lag phase can be caused by the presence of mature amyloid fibrils (seeds) in protein solution, so-called secondary nucleation. The secondary nucleation includes interaction of protein monomers with the mature fibril surface that leads to protein spatial structural changes for further amyloid fibril formation. In this work, changes of the PAP(248–286) spatial structure were obtained during the secondary nucleation phase. Pulsed-field gradient (PFG) NMR was used to characterize the behavior of monomeric PAP(248–286) in water solution after PAP(248–286) seed addition. The self-diffusion coefficient showed compactization of the peptide monomer due to fibril–monomer interactions. PAP(248–286) spatial structural changes were detected with the help of high-resolution NMR spectroscopy and molecular dynamics (MD) simulation. The folding of PAP(248–286) occurs due to backbone chain bending in the region of H270 and T275 amino acid residues. Obtained folded conformation of PAP(248–286) emerging in the secondary nucleation process is energetically favorable and retains after monomer–amyloid interaction. The structural changes are associated with localization of PAP(248–286) hydrophobic surface regions, which are probably responsible for peptide monomer–amyloid interactions.

Investigating the Effects of the POPC–POPG Lipid Bilayer Composition on PAP248–286 Binding Using CG Molecular Dynamics Simulations

“…Sexual transmission continues to be one of the primary modes of HIV transmission, with human semen serving as a vector for viral transmission, and women, in particular, at higher risk of contracting HIV through sexual contact. , One factor that has drawn the interest of the HIV research community is the role of a specific 39 amino acid-long peptide, PAP248–286, in the infection process. , PAP248–286 is derived from prostatic acid phosphatase (PAP), a protein present in high concentrations in human seminal fluid . Previous studies have suggested that PAP248–286 peptides play an important role in enhancing HIV infection by several folds. , PAP248–286 peptides aggregate to form amyloid fibrils termed semen-derived enhancers of viral infection (SEVI). ,, Unlike typical amyloid peptides, which mainly display biological activity when aggregated into fibrils, PAP248–286 has been reported to show biological activity even in its monomeric form. ,− …”

“… 5 , 8 PAP248–286 peptides aggregate to form amyloid fibrils termed semen-derived enhancers of viral infection (SEVI). 5 , 9 , 10 Unlike typical amyloid peptides, which mainly display biological activity when aggregated into fibrils, PAP248–286 has been reported to show biological activity even in its monomeric form. 5 , 11 − 15 …”