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Glycan-induced structural activation softens the human papillomavirus capsid for entry through reduction of

Yuzhen Feng1, Dominik van Bodegraven2, Alan Kádek3,4

  • 1Moleculaire Biofysica, Zernike Instituut, Rijksuniversiteit Groningen, Groningen, Netherlands.

Nature Communications
|November 21, 2024
PubMed

Insights

High-risk human papillomaviruses (HPVs) engage cells via capsid structural changes triggered by heparan sulphates (HS). Understanding HS binding reveals mechanisms for developing new anti-viral therapies against HPV infections.

Area of Science:

  • Virology
  • Structural Biology
  • Biochemistry

Background:

  • High-risk human papillomaviruses (HPVs) are oncogenic, necessitating novel antiviral strategies beyond prophylactic vaccines.
  • HPV cell entry relies on capsid structural changes initiated by interactions with cellular heparan sulphates (HS), but the precise mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms of HS-mediated HPV capsid structural activation.
  • To investigate the functional consequences of HS binding on HPV capsid conformation and infectivity.

Main Methods:

  • Utilized a combination of virological assays, hydrogen/deuterium exchange mass spectrometry (HDX-MS), and atomic force microscopy (AFM).
  • Investigated the effects of varying HS chain lengths and binding site engagement on HPV capsid structure.

Main Results:

  • HS-induced capsid activation requires a minimum HS chain length and simultaneous binding to multiple sites by a single HS molecule.
  • This interaction applies a pincer-like force, stabilizing an enlarged, softened capsid conformation with extended capsomer linkers.
  • These structural changes likely facilitate L1 proteolytic cleavage and L2 externalization, crucial steps for viral cell entry.

Conclusions:

  • The findings provide a detailed molecular understanding of HS-mediated HPV capsid activation.
  • This knowledge can inform the development of advanced prophylactic strategies targeting HPV entry mechanisms.

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