An evolutionarily mobile antigen receptor variable region gene: Doubly rearranging NAR-TcR genes in sharks

Criscitiello, Michael F.; Saltis, Mark; Flajnik, Martin F.

doi:10.1073/pnas.0507074103

Cited by 91 publications

(108 citation statements)

References 54 publications

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“…In many respects, TCR2.0 appears analogous to a TCR␦ isoform that has been described recently in sharks [nurse shark antigen receptor (NAR)-TCR] and that contains a double V domain created by tandem VDJ recombination (29). Like TCR, the nurse shark TCR␦ locus also appears to have evolved by recombination between an Ig locus (IgNAR) and TCR␦.…”

Section: Discussionmentioning

confidence: 99%

“…Like TCR, the nurse shark TCR␦ locus also appears to have evolved by recombination between an Ig locus (IgNAR) and TCR␦. In both NAR-TCR and TCR, the resulting distal V domain is most related to Ig V domains, suggesting that they may bind antigen directly like Ig and some ␥␦TCRs, rather than MHCpresented antigens such as ␣␤TCR (6,29). TCR also shares similarity to shark IgNAR and mammalian TCR␦ in by using multiple D segments in a single VDJ recombination (19,20,30).…”

Section: Discussionmentioning

confidence: 99%

“…However, similarities between marsupial TCR and shark NAR-TCR appear to be convergent evolution. For example, TCR is encoded at its own locus, whereas NAR-TCR is encoded as part of the conventional TCR␦ locus (29). Furthermore, TCR V sequences are more related to conventional VH, where the N-terminal V domain in NAR-TCR is related to Ig-NAR V genes, which do not have a known mammalian homolog (29).…”

Section: Discussionmentioning

confidence: 99%

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A unique T cell receptor discovered in marsupials

Parra

Baker

Schwarz

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

168

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T cells recognize antigens by using T cell receptors (TCRs) encoded by gene segments, called variable (V), diversity (D), and joining (J), that undergo somatic recombination to create diverse binding specificities. Four TCR chains (␣, ␤, ␥, and ␦) have been identified to date, and, as T cells develop in the thymus, they express exclusively either an ␣␤TCR or a ␥␦TCR heterodimer. Here, we show that marsupials have an additional TCR (TCR) that has V, D, and J that are either somatically recombined, as in conventional TCRs, or are already prejoined in the germ-line DNA in a manner consistent with their creation by retrotransposition. TCR does not have a known homolog in eutherian mammals but has features analogous to a recently described TCR␦ isoform in sharks. TCR is expressed in at least two mRNA isoforms that appear capable of encoding a full-length protein, both of which are transcribed in the thymus and spleen. One contains two variable domains: a somatically recombined V and a prejoined V. This appears to be the dominant isoform in peripheral lymphoid tissue. The other isoform contains only the prejoined V and is structurally more similar to conventional TCR chains, however invariant. Unlike other TCRs, TCR uses prejoined gene segments and is likely present in all marsupials. Its similarity to a TCR isoform in sharks suggests that it, or something similar, may be present in other vertebrate lineages and, therefore, may represent an ancient receptor system. evolution ͉ immune system H allmarks of the adaptive immune systems in jawed vertebrates are cells (lymphocytes) that use somatic DNA recombination to assemble the genes that encode antigen receptors. This recombination provides the means to generate a large repertoire of receptors with diverse binding specificities (1). There are two classes of antigen receptors that are used by B and T cells, respectively: Ig and T cell receptor (TCR). Although there is variation in the isotypes of Ig present, to date, all jawed vertebrates appear to have the same four TCR homologs (2, 3): TCR␣, -␤, -␥, and -␦. All contain V domains that are encoded by the variable (V), diversity (D), and joining (J) gene segments; recombined V and J encode the V domain in TCR␣ and TCR␥, whereas the TCR␤ and TCR␦ chains use V, D, and J (4). A typical TCR locus is organized in a ''translocon'' arrangement in which an array of V segments is upstream of one or more D segments (in the case of TCR␤ and TCR␦), followed by one or more J segments (4). In developing T cells, these gene segments undergo so-called VDJ recombination that is mediated, in part, by the recombination activating gene (RAG) recombinase system to assemble the exon encoding the V domain (1, 5). To date, the V, D, and J gene segments in TCR loci have always been found in a nonrecombined state in the germ-line DNA and require somatic cell recombination for expression. After recombination, T cells are then selected in the thymus to eliminate those that bind self-antigens (contributing to self-tolerance) and, in the case of ␣␤TC...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A unique T cell receptor discovered in marsupials

Parra

Baker

Schwarz

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

168

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“…A further clue to the evolutionary origin of the VNAR domain was uncovered through the work of Criscitiello and colleagues who demonstrated the existence of a VNAR TCR fusion [37]. This makes VNAR the first V domain to be integral to the biology of both Ig and TcR.…”

Section: To Be or Not To Be An Antibodymentioning

confidence: 99%

VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

Barelle¹,

Porter²

2015

Antibodies

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At 420 million years, the variable domain of New Antigen Receptors or VNARs are undoubtedly the oldest (and smallest) antigen binding single domains identified in the vertebrate kingdom. Their role as an integral part of the adaptive immune system of sharks has been well established and has served to provide a greater understanding of the evolution of humoral immunity; their cellular components and processes as well as the underlying genetic organization and molecular control mechanisms. Intriguingly, unlike the variable domain of the camelid heavy chain antibodies or VHH, VNARs do not conform to all of the characteristic properties of classical antibodies with an ancestral origin that clearly distinguishes them from true immunoglobulin antibodies. However, this uniqueness of their origin only adds to their potential as next generation therapeutic biologics with their structural and functional attributes and commercial freedom all enhancing their profile and current success. In fact their small size, remarkable stability, molecular flexibility and solubility, together with their high affinity and selectivity for target, all reinforce the potential of these domains as drug candidates. The purpose of this review is to provide an overview of the existing basic biology of these unique domains, to highlight the drug-like properties of VNARs and describe current progress in their journey towards the clinic.

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“…3 As for the V-NARs, it shows homology to Vα domain of the T-cell receptor. 5,17 Contrary to VHH, V-NAR only consists of seven β-strands instead of nine β-strands due to the truncation in FR2-CDR2 ( Figure 1F and I). This means that V-NARs have only two CDRs, ie, CDR1 and CDR3 ( Figure 1I).…”

Section: Structure Of Nanobodiesmentioning

confidence: 99%

Nanobody-derived nanobiotechnology tool kits for diverse biomedical and biotechnology applications

Wang

Fan

Shao

et al. 2016

IJN

121

107

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Owing to peculiar properties of nanobody, including nanoscale size, robust structure, stable and soluble behaviors in aqueous solution, reversible refolding, high affinity and specificity for only one cognate target, superior cryptic cleft accessibility, and deep tissue penetration, as well as a sustainable source, it has been an ideal research tool for the development of sophisticated nanobiotechnologies. Currently, the nanobody has been evolved into versatile research and application tool kits for diverse biomedical and biotechnology applications. Various nanobody-derived formats, including the nanobody itself, the radionuclide or fluorescent-labeled nanobodies, nanobody homo- or heteromultimers, nanobody-coated nanoparticles, and nanobody-displayed bacteriophages, have been successfully demonstrated as powerful nanobiotechnological tool kits for basic biomedical research, targeting drug delivery and therapy, disease diagnosis, bioimaging, and agricultural and plant protection. These applications indicate a special advantage of these nanobody-derived technologies, already surpassing the “me-too” products of other equivalent binders, such as the full-length antibodies, single-chain variable fragments, antigen-binding fragments, targeting peptides, and DNA-based aptamers. In this review, we summarize the current state of the art in nanobody research, focusing on the nanobody structural features, nanobody production approach, nanobody-derived nanobiotechnology tool kits, and the potentially diverse applications in biomedicine and biotechnology. The future trends, challenges, and limitations of the nanobody-derived nanobiotechnology tool kits are also discussed.

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An evolutionarily mobile antigen receptor variable region gene: Doubly rearranging NAR-TcR genes in sharks

Cited by 91 publications

References 54 publications

A unique T cell receptor discovered in marsupials

A unique T cell receptor discovered in marsupials

VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

Nanobody-derived nanobiotechnology tool kits for diverse biomedical and biotechnology applications

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