Making Order in the Intrinsically Disordered Regions of HIV‐1 Vif Protein

Reingewertz, Tali H.; Shalev, Deborah E.; Friedler, Assaf

doi:10.1002/9781118135570.ch8

Cited by 2 publications

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“…51 In the unbound state Vif-CTD was shown to be intrinsically disordered and undergo disorder-to-order transition upon binding. 50,52,[55][56][57][58] Multiple binding regions in Vif and A3G were reported as important for the interaction between the two (reviewed in [59][60][61]. Many of these were discovered by use of functional and biochemical analyses based on mutations, deletions and truncations, sometimes resulting in conflicting conclusions.…”

Section: Introductionmentioning

confidence: 99%

Mapping the Vif–A3G interaction using peptide arrays: A basis for anti-HIV lead peptides

Reingewertz

Britan-Rosich

Rotem‐Bamberger

et al. 2013

Bioorganic & Medicinal Chemistry

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Human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3G (A3G) is a cytidine deaminase that restricts retroviruses, endogenous retro-elements and DNA viruses. A3G plays a key role in the anti-HIV-1 innate cellular immunity. The HIV-1 Vif protein counteracts A3G mainly by leading A3G towards the proteosomal machinery and by direct inhibition of its enzymatic activity. Both activities involve direct interaction between Vif and A3G. Disrupting the interaction between A3G and Vif may rescue A3G antiviral activity and inhibit HIV-1 propagation. Here, mapping the interaction sites between A3G and Vif by peptide array screening revealed distinct regions in Vif important for A3G binding, including the N-terminal domain (NTD), C-terminal domain (CTD) and residues 83-99. The Vif-binding sites in A3G included 12 different peptides that showed strong binding to either full-length Vif, Vif CTD or both. Sequence similarity was found between Vif-binding peptides from the A3G CTD and NTD. A3G peptides were synthesized and tested for their ability to counteract Vif action. A3G 211-225 inhibited HIV-1 replication in cell culture and impaired Vif dependent A3G degradation. In vivo co-localization of full-length Vif with A3G 211-225 was demonstrated by use of FRET. This peptide has the potential to serve as an anti-HIV-1 lead compound. Our results suggest a complex interaction between Vif and A3G that is mediated by discontinuous binding regions with different affinities.

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Section: Introductionmentioning

confidence: 99%

Mapping the Vif–A3G interaction using peptide arrays: A basis for anti-HIV lead peptides

Reingewertz

Britan-Rosich

Rotem‐Bamberger

et al. 2013

Bioorganic & Medicinal Chemistry

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Prediction of virus-host protein-protein interactions mediated by short linear motifs

2017

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BackgroundShort linear motifs in host organisms proteins can be mimicked by viruses to create protein-protein interactions that disable or control metabolic pathways. Given that viral linear motif instances of host motif regular expressions can be found by chance, it is necessary to develop filtering methods of functional linear motifs. We conduct a systematic comparison of linear motifs filtering methods to develop a computational approach for predicting motif-mediated protein-protein interactions between human and the human immunodeficiency virus 1 (HIV-1).ResultsWe implemented three filtering methods to obtain linear motif sets: 1) conserved in viral proteins (C), 2) located in disordered regions (D) and 3) rare or scarce in a set of randomized viral sequences (R). The sets C,D,R are united and intersected. The resulting sets are compared by the number of protein-protein interactions correctly inferred with them – with experimental validation. The comparison is done with HIV-1 sequences and interactions from the National Institute of Allergy and Infectious Diseases (NIAID).The number of correctly inferred interactions allows to rank the interactions by the sets used to deduce them: D∪R and C. The ordering of the sets is descending on the probability of capturing functional interactions.With respect to HIV-1, the sets C∪R, D∪R, C∪D∪R infer all known interactions between HIV1 and human proteins mediated by linear motifs. We found that the majority of conserved linear motifs in the virus are located in disordered regions.ConclusionWe have developed a method for predicting protein-protein interactions mediated by linear motifs between HIV-1 and human proteins. The method only use protein sequences as inputs. We can extend the software developed to any other eukaryotic virus and host in order to find and rank candidate interactions. In future works we will use it to explore possible viral attack mechanisms based on linear motif mimicry.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1570-7) contains supplementary material, which is available to authorized users.

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Making Order in the Intrinsically Disordered Regions of HIV‐1 Vif Protein

Cited by 2 publications

References 129 publications

Mapping the Vif–A3G interaction using peptide arrays: A basis for anti-HIV lead peptides

Mapping the Vif–A3G interaction using peptide arrays: A basis for anti-HIV lead peptides

Prediction of virus-host protein-protein interactions mediated by short linear motifs

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