Structural perspectives on HIV‐1 Vif and APOBEC3 restriction factor interactions

Azimi, Farshad C.; Lee, Jeffrey E.

doi:10.1002/pro.3729

Cited by 19 publications

(22 citation statements)

References 118 publications

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“…Previous analyses of available Vif sequences have highlighted evolutionary conservation for some Vif-substrate surfaces but not others ( Azimi and Lee, 2020 ). As one would predict, residues involved in binding CBF-β and the E3-ubiquitin ligase complex are highly conserved; however, the same is not true for residues involved in APOBEC3 recognition.…”

Section: Dynamic Nature Of Vif-substrate Protein–protein Interfacesmentioning

confidence: 99%

Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest

Salamango

Harris

2021

Front. Microbiol.

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Accessory proteins are a key feature that distinguishes primate immunodeficiency viruses such as human immunodeficiency virus type I (HIV-1) from other retroviruses. A prime example is the virion infectivity factor, Vif, which hijacks a cellular co-transcription factor (CBF-β) to recruit a ubiquitin ligase complex (CRL5) to bind and degrade antiviral APOBEC3 enzymes including APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), and APOBEC3H (A3H). Although APOBEC3 antagonism is essential for viral pathogenesis, and a more than sufficient functional justification for Vif’s evolution, most viral proteins have evolved multiple functions. Indeed, Vif has long been known to trigger cell cycle arrest and recent studies have shed light on the underlying molecular mechanism. Vif accomplishes this function using the same CBF-β/CRL5 ubiquitin ligase complex to degrade a family of PPP2R5 phospho-regulatory proteins. These advances have helped usher in a new era of accessory protein research and fresh opportunities for drug development.

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Section: Dynamic Nature Of Vif-substrate Protein–protein Interfacesmentioning

confidence: 99%

Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest

Salamango

Harris

2021

Front. Microbiol.

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“…La protéine Vif est majoritairement retrouvée dans le cytoplasme et notamment au sein de complexes RNP [199,200]. Vif interagit avec le précurseur Pr55 Gag du VIH-1, indépendamment de sa capacité d'oligomérisation, ce qui aboutit à sa relocalisation au niveau de la membrane plasmique [198,199,201] directe, via les résidus R121 -I124 -L125 et R127 de Vif (domaine HCCH), et indirecte via le recrutement de l'Elongin C [45]. En effet, Vif s'associe à l'Elongin C grâce à un motif BC Box (résidus 145-155) ainsi qu'un motif 144 SLQ 146 , extrêmement conservé [250].…”

Section: Localisation Cellulaire Assemblage Et Interaction Avec Pr55unclassified

“…En outre, la structure du complexe E3-ubiquitine ligase indique que l'hélice ␣3 de Vif (résidus 119-125) est aussi en contact avec l'Elongin C [243]. Des études complémentaires ont permis de comprendre que les interactions des protéines Elongin C, Vif et Cullin 5 se stabilisent mutuellement [45], et que le motif 161 PPLP 164 de Vif permettrait son interaction avec l'Elongin B [253,254]. Toutefois, la structure résolue par Guo et al ne permet pas de confirmer ces résultats, laissant une incertitude quant aux régions d'interaction entre ces deux protéines.…”

Section: Localisation Cellulaire Assemblage Et Interaction Avec Pr55unclassified

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APOBEC3s: history of an antiviral and mutagenic protein family

Verriez¹,

Marquet²,

Paillart³

et al. 2020

Virologie

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La réponse immunitaire innée est une réponse non spécifique qui constitue la première ligne de défense en cas d'infection, notamment en permettant l'élimination des pathogènes par phagocytose ou apoptose. Au sein des cellules immunitaires, cette réponse innée se caractérise entre autres par la synthèse de protéines nommées facteurs de restriction dont le rôle est d'inhiber la réplication virale. Parmi ces facteurs, les protéines de la famille APOBEC3 (Apolipoprotein B mRNA-editing Enzyme Catalytic polypeptide-like 3 ou A3) constituent des facteurs antiviraux majeurs qui ciblent de nombreux types de virus. L'une des cibles des A3 est le virus de l'immunodéficience humaine de type 1 (VIH-1) : l'activité désaminase de certaines A3 convertit une fraction des cytidines du génome viral en uridines et perturbe son expression. Néanmoins, le VIH-1 contrecarre les A3 en exprimant la protéine Vif qui les inhibe en détournant divers mécanismes cellulaires. Par ailleurs, les APOBEC3 participent au maintien de l'intégrité génétique par l'inhibition des rétroéléments mais contribuent également à la cancérogenèse, à l'image d'A3A et A3B, deux facteurs majeurs dans ce processus. L'éventail de leurs activités, combiné aux récentes études montrant leur implication dans la régulation de virus émergents (Zika, SARS-CoV-2), permettent d'envisager les A3 ainsi que leurs partenaires viraux comme axes thérapeutiques.

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“…Without Vif present, APOBEC3 proteins interact with the HIV virion and inhibit viral replication by deamination, turning cytidines to uridines in the viral DNA (9). Vif forms a complex with the APOBEC3 proteins, which serves as a substrate for binding with Cul5-E3 ubiquitin ligase to polyubiquitinate and degrade APOBEC3 proteins (10). In order to fold and form a stable structure, Vif interacts with different proteins: Elongin-B (EloB), Elongin-C (EloC) at its C-terminus, and core-binding factor subunit-β (CBFβ) at its N-terminus (11)(12)(13), forming the VCBC complex.…”

Section: Introductionmentioning

confidence: 99%

High-Speed AFM directly visualizes conformational dynamics of the HIV-Vif protein complex

Pan

Shlyakhtenko

Lyubchenko

2020

Preprint

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Keywords:High-Speed Atomic Force Microscopy (HS-AFM), virus infectivity factor (Vif), singlestranded DNA (ssDNA), double-stranded DNA (dsDNA),the human APOBEC3 family of cytidine deaminases (APOBEC3) proteins, Vif-Elongin-C, Elongin-B-CBF-β complex (VCBC), human immunodeficiency virus (HIV), acquired immune deficiency syndrome (AIDS). AbstractViral infectivity factor (Vif) is a protein that is essential for the replication of the HIV-1 virus. The key function of Vif is to disrupt the antiviral activity of APOBEC3 proteins, which mutate viral nucleic acids. Inside the cell, Vif binds to the host cell proteins Elongin-C, Elongin-B, and CBF-β, forming a fourprotein complex called VCBC. The structure of VCBC in complex with the Cullin5 (Cul5) protein has been solved by X-ray crystallography, and recently, using molecular dynamic (MD) simulations, the dynamics of VCBC and VCBC-Cul5 complexes were characterized. Here, we applied time-lapse highspeed atomic force microscopy (HS-AFM) to visualize the conformational changes of the VCBC complex. We determined the three most favorable conformations of the VCBC complex, which we identified as triangle, dumbbell, and globular structures. In addition, we characterized the dynamics of each of these structures. While our data show a very dynamic behavior for all these structures, we found the triangle and dumbbell structures to be the most dynamic. These findings provide insight into the structure and dynamics of the VCBC complex and support further research into the improvement of HIV treatment, as Vif is essential for virus survival in the cell.

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Structural perspectives on HIV‐1 Vif and APOBEC3 restriction factor interactions

Cited by 19 publications

References 118 publications

Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest

Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest

APOBEC3s: history of an antiviral and mutagenic protein family

High-Speed AFM directly visualizes conformational dynamics of the HIV-Vif protein complex

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