Identification of functional sites on bovine leukemia virus envelope glycoproteins using structural and immunological data

Callebaut, Isabelle; Portetelle, Daniel; Burny, Arsène; Mornon, Jean‐Paul

doi:10.1111/j.1432-1033.1994.tb18879.x

Cited by 19 publications

(24 citation statements)

References 51 publications

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“…Our model of the BLV RBD has some similarities to and some major differences from the one developed by Callebaut et al (9) using hydrophobic cluster analysis (HCA) prior to solution of the F-MuLV RBD structure. The earlier BLV model was based partly on the structure of the influenza virus hemagglutinin type 1 (HA-1) protein and partly on the ␣3 domain of HLA-A2 (major histocompatibility complex class I).…”

Section: Fig 7 (A)mentioning

confidence: 99%

“…Since HCA does not generate specific alignments and does not predict structural elements, our alignment is not directly comparable to the previous analysis (9). However, since HCA can identify patterns of hydrophobic residues, we examined BLV and F-MuLV RBD sequences for conservation of hydrophobic clusters that could represent conserved segments to use as a basis for an alignment.…”

Section: Fig 7 (A)mentioning

confidence: 99%

“…Two models of BLV SU have previously been developed, the first based on proteinfolding patterns (39) and the second based on hydrophobic cluster analysis and comparison with the known structures of influenza virus hemagglutinin-1 protein and the HLA-A2 protein of the human major histocompatibility complex (9).…”

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confidence: 99%

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Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

Johnston

Albritton

Radke

2002

J Virol

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Functional domains of the strikingly conserved envelope (Env) glycoproteins of bovine leukemia virus (BLV) and its close relative, human T-cell leukemia virus type 1 (HTLV-1), are still being defined. We have used BLV Env protein variants to gain insights into the structure and function of this important determinant of viral infectivity. Each of 23 different single amino acid variants found in cDNA clones of env transcripts present after short-term culture of peripheral blood mononuclear cells from BLV-infected sheep was expressed in COS-1 cells and tested for the ability to mediate cell fusion and to be cleaved to surface (SU) and transmembrane (TM) protein subunits. Of 11 Env variants that failed to induce syncytia or did so poorly, 7 contained changes in amino acids identical or chemically conserved in the HTLV-1 Env protein. These seven included the four variants that showed aberrant proteolytic cleavage and poor cell surface expression, underscoring their importance for Env structure. Ten of 12 variants that retained wild-type syncytium-inducing ability clustered in the N-terminal half of BLV SU, which forms the putative receptor-binding domain (RBD). Several variants in the RBD showed evidence of subtle misfolding, as judged by reduced binding to monoclonal antibodies recognizing conformational epitopes F, G, and H formed by the N terminus of SU. We modeled the BLV RBD by aligning putative structural elements with known elements of the ecotropic Friend murine leukemia virus RBD monomer. All the variant RBD residues but one are exposed on the surface of this BLV model. These variants as well as function-altering, antibody-reactive residues defined by other investigators group on one face of the molecular model. They are strikingly absent from the opposite face, implying that it is likely to face inward in Env complexes. This surface might interact with the C-terminal domain of SU or with an adjacent monomer in the Env oligomer. This location suggests an orientation for the monomer of ecotropic Friend murine leukemia virus RBD.Envelope (Env) proteins confer infectivity on retroviral particles. Oligomers of these proteins bind to receptors on the surfaces of host cells and mediate entry of the viral genome into the cell. The Env protein complex is composed of surface glycoprotein (SU) subunits, which are anchored to virions by their association with transmembrane (TM) protein subunits. SU molecules recognize and bind to cellular receptors, thereby initiating a complex series of conformational changes that lead to fusion of viral and cellular membranes by TM oligomers (reviewed in reference 30). Upon successful synthesis of the DNA provirus and its integration into host cell DNA, expression of viral genes ensues. When the newly synthesized polyprotein Env precursor is cleaved in the Golgi apparatus of the virus-producing host cell, SU and TM subunits remain associated in a metastable state (18). Oligomers of mature Env proteins are transported to the cell surface membrane, where they can be incorporated into b...

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Section: Fig 7 (A)mentioning

confidence: 99%

Section: Fig 7 (A)mentioning

confidence: 99%

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Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

Johnston

Albritton

Radke

2002

J Virol

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“…Conservation of TM proteins from several viruses, as supported by sequence alignments and crystallographic studies, underlines common features in the structure and the mode of action of retroviral fusion proteins (15,32,33,47). In particular, the HTLV-1 gp46 and BLV gp51 heads possibly interacting with the cellular receptor have been predicted to adopt a structure corresponding to the overall topology of constant immunoglobulin domains (15).…”

mentioning

confidence: 99%

“…In particular, the HTLV-1 gp46 and BLV gp51 heads possibly interacting with the cellular receptor have been predicted to adopt a structure corresponding to the overall topology of constant immunoglobulin domains (15).…”

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confidence: 99%

Bovine Leukemia Virus SU Protein Interacts with Zinc, and Mutations within Two Interacting Regions Differently Affect Viral Fusion and Infectivity In Vivo

Gatot

Callebaut

Lint

et al. 2002

J Virol

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Bovine leukemia virus (BLV) and human T-cell lymphotropic virus type 1 (HTLV-1) belong to the genus of deltaretroviruses. Their entry into the host cell is supposed to be mediated by interactions of the extracellular (SU) envelope glycoproteins with cellular receptors. To gain insight into the mechanisms governing this process, we investigated the ability of SU proteins to interact with specific ligands. In particular, by affinity chromatography, we have shown that BLV SU protein specifically interacted with zinc ions. To identify the protein domains involved in binding, 16 peptides distributed along the sequence were tested. Two of them appeared to be able to interact with zinc. To unravel the role of these SU regions in the biology of the virus, mutations were introduced into the env gene of a BLV molecular clone in order to modify residues potentially interacting with zinc. The fusogenic capacity of envelope mutated within the first zinc-binding region (104 to 123) was completely abolished. Furthermore, the integrity of this domain was also required for in vivo infectivity. In contrast, mutations within the second zinc-binding region (218 to 237) did not hamper the fusogenic capacity; indeed, the syncytia were even larger. In sheep, mutations in region 218 to 237 did not alter infectivity or viral spread. Finally, we demonstrated that the envelope of the related HTLV-1 was also able to bind zinc. Interestingly, zinc ions were found to be associated with the receptor-binding domain (RBD) of Friend murine leukemia virus (Fr-MLV) SU glycoprotein, further supporting their relevance in SU structure. Based on the sequence similarities shared with the Fr-MLV RBD, whose three-dimensional structure has been experimentally determined, we located the BLV zinc-binding peptide 104-123 on the opposite side of the potential receptor-binding surface. This observation supports the hypothesis that zinc ions could mediate interactions of the SU RBD either with the C-terminal part of SU, thereby contributing to the SU structural integrity, or with a partner(s) different from the receptor.Bovine leukemia virus (BLV) and human T-cell lymphotropic virus type 1 (HTLV-1) belong to the genus of deltaretroviruses (70). HTLV-1 is the etiologic agent of adult T-cell leukemia (40,58,76,83) and HTLV-1-associated myelopathy or tropical spastic paraparesis (36,43,56). BLV causes enzootic bovine leukemia, a chronic and contagious disease that evolves over an extended period of time, with tumors developing in a small number of infected cattle but in the majority of infected sheep (12, 46, 52, 54). One of the main interests of the BLV system is that it allows direct experimentation in cattle and sheep as a model for HTLV-1-induced pathogenesis (77,78).Like other retroviruses, HTLV-1 and BLV enter the host cell through interactions of their envelope glycoproteins with specific cellular receptors, a process leading to fusion of the virus and cell membranes and followed by delivery of the viral genome into the cytoplasm. To date, these receptors r...

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Identification of exposed epitopes on the envelope glycoproteins of human T-cell lymphotropic virus type I (HTLV-I)

et al. 1998

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Several lines of evidence underscore the important role of the humoral response specific for HTLV‐I envelope protein in the protection against viral infection. One approach to producing efficient immunogens is to synthesize peptides corresponding to the primary amino‐acid sequence of neutralizing epitopes found in the external sub‐unit gp46. In this study, we have selected synthetic peptides overlapping the major linear neutralizing determinants described earlier and used them as immunogens in rabbits and mice. All rabbit polyclonal antisera raised against peptides recognized epitopes in a denaturated context as well as MAbs raised against the HB peptide (aa287‐311). By contrast, synthetic peptides O (aa89‐110), HH (aa190‐209), T (aa190‐212) and HB (aa287‐311) have generated antibodies efficiently binding their epitopes in a native context, suggesting that these domains are well exposed both at the heterodimer and at the oligomer surface. None of the antibodies induced by synthetic peptides show in vitro neutralizing properties, even those with a good capacity to bind the native form of HTLV‐I envelope proteins. Int. J. Cancer 75:804–813, 1998.© 1998 Wiley‐Liss, Inc.

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Identification of functional sites on bovine leukemia virus envelope glycoproteins using structural and immunological data

Cited by 19 publications

References 51 publications

Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

Bovine Leukemia Virus SU Protein Interacts with Zinc, and Mutations within Two Interacting Regions Differently Affect Viral Fusion and Infectivity In Vivo

Identification of exposed epitopes on the envelope glycoproteins of human T-cell lymphotropic virus type I (HTLV-I)

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