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.
Highlights
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
It can occur in the form of “simple” dimers or higher order oligomers of cytokines, chemokines and growth factors that favour receptor clustering at the cell surface and transduction of the signal that, in turn, trigger cytoskeletal rearrangements, cell movement and other cellular responses including proliferation and survival involved in physiological and pathological processes such as immune responses, angiogenesis and cancerogenesis[14,28,29,30,31]
Some “amyloidogenic” proteins are endowed with the propensity to change conformation from an α-helix to β-sheet, tending to misfold and to form aspecific large aggregates responsible of the pathogenesis of many human diseases, including neurodegenerative pathologies such as Alzheimer and Parkinson’ disease[32]
Summary
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. Beside p17, HSPGs act as receptors for HIV-1 gp12011 and Tat[12] while free heparin promotes Tat oligomerization and biological activity[13]. HSPGs act as co-receptor for many other viral proteins and cytokines, promoting their oligomerization required for receptors clustering and activation[14]. Due to the presence of “coiled coil” sequences, p17 tends to misfold[21], behaving as an “amyloidogenic” protein that forms toxic assemblies in the brain that have been demonstrated to contribute to AIDS-associated neurodegeneration[4]. The capacity of p17 to oligomerize and to bind to heparin/HSPGs, along with the involvement of the GAG in the process of oligomerization of many cytokines prompted us to study the effect of heparin/ HSPGs on p17 oligomerization and biological consequences by adopting a multidisciplinary approach including bioinformatics, biochemical and cell-based models
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