Abstract:Immunoglobulin and T-cell receptor (TCR) molecules are central to the adaptive immune system. Sequence conservation, similarities in domain structure, and usage of similar recombination signal sequences and recombination machinery indicate that there was probably a time during evolution when an ancestral receptor diverged to the modern-day immunoglobulin and TCR. Other molecules that undergo rearrangement have not been described in vertebrates, nor have intermediates been identified that have features of both … Show more
“…A minority of V NAR s (type IV) bear only the single canonical disulfide linkage. As for V H Hs, most V NAR Cys residues in CDR1, FR2 and FR4 are probably encoded in the germline and non-canonical disulfide linkages are formed during primary repertoire development 4,27,28 Although the precise roles of non-canonical disulfide linkages in sdAb structure and function remain unclear, these linkages very likely influence sdAb paratope structure, since patterns of antigen-driven somatic hypermutation appear to vary depending on their presence and location. 27 10.1080/19420862.2018.1489633-F0002Fig 2.Properties of sdAb vs .…”
“…in 1989, 2 and several years later, naturally-occurring antibodies lacking light chains were discovered in dromedary camels 3 and nurse sharks. 4 The ~12–15 kDa variable domains of these antibodies (V H Hs and V NAR s, respectively; Figure 1) can be produced recombinantly and can recognize antigen in the absence of the remainder of the antibody heavy chain. The modular nature of V H Hs and V NAR s has been widely and productively exploited in the development of antibody-based drugs (reviewed in Ref.…”
Section: Introductionmentioning
confidence: 99%
“…24 Some V H H genes encode non-canonical disulfide linkages formed between cysteine residue pairs (CDR1-CDR3, FR2-CDR3, CDR2-CDR3 or CDR3-CDR3; see Box 2). V NAR s, the variable domains of cartilaginous fish Ig new antigen receptors, share sequence homology with T-cell receptor and Ig light chain genes 4 and may be descended from Ig-superfamily cell-surface receptors. 26 Compared with Ig V H domains, V NAR s lack two β strands (C ’ and C ’’ ) and consequently CDR2 is absent, although loops connecting the C-D and D-E strands (HV2 and HV4, respectively) can make contact with antigen.…”
Section: Introductionmentioning
confidence: 99%
“…During B-cell development, V NAR domains are rearranged from a small number of loci (perhaps only three) distinct from those encoding other types of Ig molecules detectable in serum (IgM, IgW). Each locus contains one V gene, two or three D genes and one J gene and thus primary repertoire diversity is almost entirely CDR3-based: 4 since V NAR CDR3 loops are formed through either three or four independent rearrangement events, these tend to be long. 27 Unlike the V H domains of IgMs and IgWs, V NAR s accrue somatic hypermutations upon encounter with antigen primarily in CDR1 and CDR3 but also in HV2 and HV4.…”
Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH:VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. Here, we comprehensively surveyed the evidence in support of this hypothesis. We found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies: sdAb paratopes have smaller molecular surface areas and diameters, more commonly have non-canonical CDR1 and CDR2 structures, and have elongated CDR3 length distributions, but have similar amino acid compositions and are no more extended (interatomic distance measured from CDR base to tip) than conventional antibody paratopes. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.
“…A minority of V NAR s (type IV) bear only the single canonical disulfide linkage. As for V H Hs, most V NAR Cys residues in CDR1, FR2 and FR4 are probably encoded in the germline and non-canonical disulfide linkages are formed during primary repertoire development 4,27,28 Although the precise roles of non-canonical disulfide linkages in sdAb structure and function remain unclear, these linkages very likely influence sdAb paratope structure, since patterns of antigen-driven somatic hypermutation appear to vary depending on their presence and location. 27 10.1080/19420862.2018.1489633-F0002Fig 2.Properties of sdAb vs .…”
“…in 1989, 2 and several years later, naturally-occurring antibodies lacking light chains were discovered in dromedary camels 3 and nurse sharks. 4 The ~12–15 kDa variable domains of these antibodies (V H Hs and V NAR s, respectively; Figure 1) can be produced recombinantly and can recognize antigen in the absence of the remainder of the antibody heavy chain. The modular nature of V H Hs and V NAR s has been widely and productively exploited in the development of antibody-based drugs (reviewed in Ref.…”
Section: Introductionmentioning
confidence: 99%
“…24 Some V H H genes encode non-canonical disulfide linkages formed between cysteine residue pairs (CDR1-CDR3, FR2-CDR3, CDR2-CDR3 or CDR3-CDR3; see Box 2). V NAR s, the variable domains of cartilaginous fish Ig new antigen receptors, share sequence homology with T-cell receptor and Ig light chain genes 4 and may be descended from Ig-superfamily cell-surface receptors. 26 Compared with Ig V H domains, V NAR s lack two β strands (C ’ and C ’’ ) and consequently CDR2 is absent, although loops connecting the C-D and D-E strands (HV2 and HV4, respectively) can make contact with antigen.…”
Section: Introductionmentioning
confidence: 99%
“…During B-cell development, V NAR domains are rearranged from a small number of loci (perhaps only three) distinct from those encoding other types of Ig molecules detectable in serum (IgM, IgW). Each locus contains one V gene, two or three D genes and one J gene and thus primary repertoire diversity is almost entirely CDR3-based: 4 since V NAR CDR3 loops are formed through either three or four independent rearrangement events, these tend to be long. 27 Unlike the V H domains of IgMs and IgWs, V NAR s accrue somatic hypermutations upon encounter with antigen primarily in CDR1 and CDR3 but also in HV2 and HV4.…”
Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH:VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. Here, we comprehensively surveyed the evidence in support of this hypothesis. We found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies: sdAb paratopes have smaller molecular surface areas and diameters, more commonly have non-canonical CDR1 and CDR2 structures, and have elongated CDR3 length distributions, but have similar amino acid compositions and are no more extended (interatomic distance measured from CDR base to tip) than conventional antibody paratopes. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.
“…Both V(D)J recombination and SHM are utilized by all of the species that have been examined, whereas gene conversion has a major role only in birds 1,8,9 . Additionally, more than 10 genes encoding different Ig classes, such as IgM, IgD (IgW), IgNAR, IgZ (IgT), IgA (IgX), IgY, IgF, IgO, IgG and IgE, have been identified in various species 3,[10][11][12][13][14][15][16][17][18][19][20] , and IgG and IgA are further diversified into a variable number of subclasses in mammalian species. Differential diversification of the Ig classes or subclasses may have arisen from a long evolutionary period of environmental selection pressure, thus conferring survival advantages.…”
Crocodilians are a group of reptiles that are closely related to birds and are thought to possess a strong immune system. Here we report that the IgH locus in the Siamese crocodile and the Chinese alligator contains multiple m genes, in contrast to other tetrapods. Both the m2 and m3 genes are expressed through class-switch recombination involving the switch region and germline transcription. Both IgM1 and IgM2 are present in the serum as polymers, which implies that IgM class switching may have significant roles in humoural immunity. The crocodilian a genes are the first IgA-encoding genes identified in reptiles, and these genes show an inverted transcriptional orientation similar to that of birds. The identification of both a and d genes in crocodilians suggests that the IgH loci of modern living mammals, reptiles and birds share a common ancestral organization.
The humoral immune response of camels, dromedaries and llamas includes functional antibodies formed by two heavy chains and no light chains. The amino acid sequence of the variable domain of the naturally occurring heavy-chain antibodies reveals the necessary adaptations to compensate for the absence of the light chain. In contrast to the conventional antibodies, a large proportion of the heavy-chain antibodies acts as competitive enzyme inhibitors. Studies on the dromedary immunoglobulin genes start to shed light on the ontogeny of these heavy-chain antibodies. The presence of the heavy-chain antibodies and the possibility of immunizing a dromedary allows for the production of antigen binders consisting of a single domain only. These minimal antigen-binding fragments are well expressed in bacteria, bind the antigen with affinity in the nM range and are very stable. We expect that such camelid single domain antibodies will find their way into a number of biotechnological or medical applications. The structure of the camelid single domain is homologous to the human VH, however, the antigen-binding loop structures deviate fundamentally from the canonical structures described for human or mouse VHs. This has two additional advantages: (1) the camel or llama derived single domain antibodies might be an ideal scaffold for anti-idiotypic vaccinations; and (2) the development of smaller peptides or peptide mimetic drugs derived from of the antigen binding loops might be facilitated due to their less complex antigen binding site.
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