Structure of the Core Postfusion Porcine Endogenous Retrovirus Fusion Protein

Dean, Trevor T.; Serrão, Vitor Hugo Balasco; Lee, Jeffrey E.

doi:10.1128/mbio.02920-21

Cited by 6 publications

(5 citation statements)

References 80 publications

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“…Fusion peptides are at or near the N-terminus of the fusion subunit [ 26 ]. Class I fusion proteins are produced in a precursor form and then cleaved into TM and SU subunits by furin protease to liberate the N-terminal hydrophobic fusion peptide that would be inserted into the cell membrane [ 44 , 45 ]. When fusion commences, major structural rearrangements lead to the assembly of head-domain HR segments into a central trimeric α-helical coiled-coil structure, displacing the fusion peptide in the direction of the host cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Essential role of an ERV-derived Env38 protein in adaptive humoral immunity against an exogenous SVCV infection in a zebrafish model

Hong

Bai

et al. 2023

PLoS Pathog

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Endogenous retroviruses (ERVs) are the relics of ancient retroviruses occupying a substantial fraction of vertebrate genomes. However, knowledge about the functional association of ERVs with cellular activities remains limited. Recently, we have identified approximately 3,315 ERVs from zebrafish at genome-wide level, among which 421 ERVs were actively expressed in response to the infection of Spring viraemia of carp virus (SVCV). These findings demonstrated the previously unrecognized activity of ERVs in zebrafish immunity, thereby making zebrafish an attractive model organism for deciphering the interplay among ERVs, exogenous invading viruses, and host immunity. In the present study, we investigated the functional role of an envelope protein (Env38) derived from an ERV-E5.1.38-DanRer element in zebrafish adaptive immunity against SVCV in view of its strong responsiveness to SVCV infection. This Env38 is a glycosylated membrane protein mainly distributed on MHC-II+ antigen-presenting cells (APCs). By performing blockade and knockdown/knockout assays, we found that the deficiency of Env38 markedly impaired the activation of SVCV-induced CD4+ T cells and thereby led to the inhibition of IgM+/IgZ+ B cell proliferation, IgM/IgZ Ab production, and zebrafish defense against SVCV challenge. Mechanistically, Env38 activates CD4+ T cells by promoting the formation of pMHC-TCR-CD4 complex via cross-linking MHC-II and CD4 molecules between APCs and CD4+ T cells, wherein the surface subunit (SU) of Env38 associates with the second immunoglobin domain of CD4 (CD4-D2) and the first α1 domain of MHC-IIα (MHC-IIα1). Notably, the expression and functionality of Env38 was strongly induced by zebrafish IFNφ1, indicating that env38 acts as an IFN-stimulating gene (ISG) regulated by IFN signaling. To the best of our knowledge, this study is the first to identify the involvement of an Env protein in host immune defense against an exogenous invading virus by promoting the initial activation of adaptive humoral immunity. It improved the current understanding of the cooperation between ERVs and host adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

Essential role of an ERV-derived Env38 protein in adaptive humoral immunity against an exogenous SVCV infection in a zebrafish model

Hong

Bai

et al. 2023

PLoS Pathog

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“…Notably, analyses of protein structures from genetically distinct viruses revealed significant structural conservation despite a high degree of sequence deviation. 41,42 These results suggest that these proteins share a common mechanism of action; thus, anti-viral strategies may be repurposed to inhibit homologous proteins across different viral families. This idea is particularly interesting when considering PDCs as highly specific peptides can be designed to tailor therapies for particular viruses.…”

Section: Anti-viral Peptide−drug Conjugatesmentioning

confidence: 96%

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Dean,

Jelú-Reyes,

Allen

et al. 2024

J. Med. Chem.

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Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide−drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide−drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody−drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide−drug conjugate design and optimization, such as peptide/smallmolecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide−drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms. ■ SIGNIFICANCE• Juxtaposition of peptide−drug conjugates and antibody−drug conjugates with a focus on challenges that can be overcome with peptide−drug conjugate strategies. • Considerations for the design and optimization of peptide−drug conjugates. • Analysis of several peptide−drug conjugate series that demonstrate effectiveness toward drug-resistant infections and complex disease states.

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“…High resolution structural insights into the gamma-type Env include crystal structures of at least three unbound RBDs ( Figure 4 ), as well as papers describing structures of a PRR and the post-fusion conformation of TM [ 23 , 108 , 109 , 112 , 225 , 226 , 227 ]. There are also at least two cryo-EM reconstructions of gammaretroviral Envs bound to their cognate receptors [ 117 , 228 ].…”

Section: Receptor Interactions Of Gamma-type Envsmentioning

confidence: 99%

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

Hogan

Johnson

2023

Viruses

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After the onset of the AIDS pandemic, HIV-1 (genus Lentivirus) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the Alpharetrovirus, Gammaretrovirus and Deltaretrovirus genera. For example, oncogenic model system viruses such as Rous sarcoma virus (RSV, Alpharetrovirus), murine leukemia virus (MLV, Gammaretrovirus) and human T-cell leukemia viruses (HTLV-I and HTLV-II, Deltaretrovirus) encode Envs that are structurally and functionally distinct from HIV Env. We refer to these as Gamma-type Envs. Gamma-type Envs are probably the most widespread retroviral Envs in nature. They are found in exogenous and endogenous retroviruses representing a broad spectrum of vertebrate hosts including amphibians, birds, reptiles, mammals and fish. In endogenous form, gamma-type Envs have been evolutionarily coopted numerous times, most notably as placental syncytins (e.g., human SYNC1 and SYNC2). Remarkably, gamma-type Envs are also found outside of the Retroviridae. Gp2 proteins of filoviruses (e.g., Ebolavirus) and snake arenaviruses in the genus Reptarenavirus are gamma-type Env homologs, products of ancient recombination events involving viruses of different Baltimore classes. Distinctive hallmarks of gamma-type Envs include a labile disulfide bond linking the surface and transmembrane subunits, a multi-stage attachment and fusion mechanism, a highly conserved (but poorly understood) “immunosuppressive domain”, and activation by the viral protease during virion maturation. Here, we synthesize work from diverse retrovirus model systems to illustrate these distinctive properties and to highlight avenues for further exploration of gamma-type Env structure and function.

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Structure of the Core Postfusion Porcine Endogenous Retrovirus Fusion Protein

Abstract: Class I viral fusion proteins represent a diverse group of fusogens that catalyze membrane fusion. Although structural studies have focused on those from exogenous viruses, ancient retroviral infections of germ line cells have immortalized ancient fusogens in eukaryotic genomes.

Cited by 6 publications

References 80 publications

Essential role of an ERV-derived Env38 protein in adaptive humoral immunity against an exogenous SVCV infection in a zebrafish model

Essential role of an ERV-derived Env38 protein in adaptive humoral immunity against an exogenous SVCV infection in a zebrafish model

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

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