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.

Bugatti, A., Paiardi, G., Urbinati, C., Chiodelli, P., Orro, A., Uggeri, M., Milanesi, L., Caruso, A., Caccuri, F., D'Ursi, P., Rusnati, M., Heparin and heparan sulfate proteoglycans promote HIV-1 p17 matrix protein oligomerization: computational, biochemical and biological implications, <<SCIENTIFIC REPORTS>>, 2019; 9 (1): 15768-N/A. [doi:10.1038/s41598-019-52201-w] [https://hdl.handle.net/10807/229414]

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

Chiodelli, Paola;
2019

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.
2019
Inglese
Bugatti, A., Paiardi, G., Urbinati, C., Chiodelli, P., Orro, A., Uggeri, M., Milanesi, L., Caruso, A., Caccuri, F., D'Ursi, P., Rusnati, M., Heparin and heparan sulfate proteoglycans promote HIV-1 p17 matrix protein oligomerization: computational, biochemical and biological implications, <<SCIENTIFIC REPORTS>>, 2019; 9 (1): 15768-N/A. [doi:10.1038/s41598-019-52201-w] [https://hdl.handle.net/10807/229414]
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