Heparin and heparan sulfate proteoglycans promote HIV-1 p17 matrix protein oligomerization: computational, biochemical and biological implications

Antonella Bugatti, Giulia Paiardi, Chiara Urbinati, Paola Chiodelli, Alessandro Orro, Matteo Uggeri, Luciano Milanesi, Arnaldo Caruso, Francesca Caccuri, Pasqualina D’Ursi, Marco Rusnati

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

p17 matrix protein released by HIV+ cells interacts with leukocytes heparan sulfate proteoglycans (HSPGs), CXCR1 and CXCR2 exerting different cytokine-like activities that contribute to AIDS pathogenesis. Since the bioactive form of several cytokines is represented by dimers/oligomers and oligomerization is promoted by binding to heparin or HSPGs, here we evaluated if heparin/HSPGs also promote p17 oligomerization. Heparin favours p17 dimer, trimer and tetramer assembly, in a time- and biphasic dose-dependent way. Heparin-induced p17 oligomerization is of electrostatic nature, being it prevented by NaCl, by removing negative sulfated groups of heparin and by neutralizing positive lysine residues in the p17 N-terminus. A new computational protocol has been implemented to study heparin chains up to 24-mer accommodating a p17 dimer. Molecular dynamics show that, in the presence of heparin, two p17 molecules undergo conformational modifications creating a continuous "electropositive channel" in which heparin sulfated groups interact with p17 basic amino acids, promoting its dimerization. At the cell surface, HSPGs induce p17 oligomerization, as demonstrated by using B-lymphoblastoid Namalwa cells overexpressing the HSPG Syndecan-1. Also, HSPGs on the surface of BJAB and Raji human B-lymphoblastoid cells are required to p17 to induce ERK1/2 activation, suggesting that HS-induced oligomerization plays a role in p17-induced lymphoid dysregulation during AIDS.
Lingua originaleEnglish
pagine (da-a)15768-N/A
RivistaScientific Reports
Volume9
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • HIV-1
  • oligomerization
  • heparan sulfate proteoglycan
  • p17

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