Protein Structural Disorder Of The Envelope V3 Loop Contributes To The Switch In Human Immunodeficiency Virus Type 1 Cell Tropism

Abstract

15Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an 16 intrinsically disordered (unstructured/disordered) protein as it contains regions 17 that do not fold into well-defined protein structures. These disordered regions 18 play important roles in HIV's life cycle, particularly, V3 loop-dependent cell entry, 19 which determines how the virus uses two coreceptors on immune cells, the 20 chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most 21 infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the 22 not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/130161 doi: bioRxiv preprint first posted online Apr. 24, 2017; 2 majority of infections. Why does this 'rewiring' event occur in HIV-1 infected 23 patients? As changes in the charge of the V3 loop are associated with this 24 receptor switch and it has been suggested that charged residues promote 25 structure disorder, we hypothesise that the intrinsic disorder of the V3 loop 26 plays a role in determining cell tropism. To test this we use three independent 27 data sets of gp120 to analyse V3 loop disorder. We find that the V3 loop of X4 28 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, 29 while R5X4 virus has the lowest. These results indicate that structural disorder 30 plays an important role in determining HIV-1 cell tropism and CXCR4 binding. 31We speculate that changes in N-linked glycosylation associated with tropism 32 change (from R5 to X4) are required to stabilise the V3 loop with increased 33 disorder tendency during HIV-1 evolution. We discuss the potential evolutionary 34 mechanisms leading to the fixation of disorder promoting mutations and the 35 adaptive potential of protein structural disorder in viral host adaptation. 36

N‐glycoproteins exhibit a positive expression level–evolutionary rate correlation

“…Sites predicted to be involved in N‐linked glycosylation have been shown to appear in regions under positive selection and co‐evolution (Jiang, Feyertag, & Robertson, ; Jiang et al., ). We thus considered the possibility that N‐glycoproteins under positive selection might drive these observations (if N‐glycoproteins under positive selection tended to be highly expressed).…”

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

“…Here, the green-and-white bar in the middle of each plot shows the predicted disorder agreement between nine predictors, with green parts corresponding to disordered regions by consensus. Yellow bar shows the location of the predicted disorder-based binding sites (molecular recognition features, MoRFs), whereas colored circles at the bottom of the plot show location of various PTMs: phosphorylation (red), acetylation (yellow), glycosylation (orange), ubiquitination (violet), nitrosylation (light blue), methylation (dark blue), and SUMOylation (green) the highest intrinsic disorder tendency is present in the V3 loop of X4 virus, whereas R5X4 virus is characterized by the lowest disorder propensity in this loop [161]. Therefore, these data clearly indicated that structural disorder in the V3 loop that constitutes just 3.6% of the gp120 plays an important role in HIV-1 cell tropism and CXCR4 binding [161].…”

<p>G1-S4 or G2-S16 carbosilan dendrimer in combination with Platycodin D as a promising vaginal microbicide candidate with contraceptive activity</p>

“…In the case of X4-HIV-1 NL.4.3 isolates, the V3 region of gp120 is more exposed at the viral surface. 32 Thus, the availability of positive charges with which the dendrimers can interact is greater than in the case of the R5-HIV-1 NL.AD8 isolate, which use CCR5 as coreceptor and in which V3 region appears to have a more internal arrangement in the virus membrane ( Figure 2).…”