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

Aleksandra M Kusova1,2, Aydar R Yulmetov1, Dmitriy S Blokhin1

  • 1Kazan Federal University, Kremlevskaya Str., 18, 420008 Kazan, Russia.

Biochemistry
|May 29, 2023
PubMed

Insights

The study reveals how prostatic acid phosphatase (PAP) peptide monomers change shape during amyloid fibril formation. These structural changes, driven by interactions with existing fibrils, are crucial for the secondary nucleation process.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Biophysics

Background:

  • Prostatic acid phosphatase (PAP) is a human seminal plasma protein.
  • The C-terminal region of PAP, specifically PAP(248-286), forms amyloid fibrils known as semen-derived enhancer of viral infection (SEVI).
  • SEVI is abundant in semen and plays a role in viral infection enhancement.

Purpose of the Study:

  • To investigate the initial stages of PAP(248-286) amyloid fibril formation.
  • To characterize the structural changes of PAP(248-286) monomers during secondary nucleation.
  • To understand the molecular mechanisms underlying fibril-monomer interactions.

Main Methods:

  • Pulsed-field gradient (PFG) NMR spectroscopy to study monomer behavior in solution.
  • High-resolution NMR spectroscopy to detect structural changes.
  • Molecular dynamics (MD) simulations to model peptide conformation.

Main Results:

  • Secondary nucleation involves interactions between PAP(248-286) monomers and mature fibrils.
  • PFG NMR revealed monomer compactization upon interaction with fibril seeds.
  • NMR and MD simulations showed PAP(248-286) folding via backbone bending around H270 and T275.
  • The folded conformation is energetically favorable and stable after monomer-amyloid interaction.
  • Structural changes involve the exposure of hydrophobic regions, facilitating monomer-amyloid interactions.

Conclusions:

  • The study elucidates the structural transformation of PAP(248-286) monomers during secondary nucleation.
  • Fibril-monomer interactions induce a stable, folded conformation in PAP(248-286).
  • Hydrophobic interactions are key to the observed monomer-amyloid binding mechanism.

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