Antibody structure and the evolution of immunoglobulin V gene segments

Kirkham, Perry M.; Schroeder, Harry W.

doi:10.1006/smim.1994.1045

Cited by 107 publications

(62 citation statements)

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“…Indeed, the CRR boundaries reported in this article are even more closely aligned with refinements of CDR reported by others (26). CRRs are defined by measuring physical distance between atoms within crystal structures, whereas CDRs are defined by Ig gene sequence variability.…”

Section: Comparison Of Crr With Cdrsupporting

confidence: 84%

Antibody and Antigen Contact Residues Define Epitope and Paratope Size and Structure

Stave¹,

Lindpaintner²

2013

The Journal of Immunology

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A total of 111 Ag–Ab x-ray crystal structures of large protein Ag epitopes and paratopes were analyzed to inform the process of eliciting or selecting functional and therapeutic Abs. These analyses illustrate that Ab contact residues (CR) are distributed in three prominent CR regions (CRR) on L and H chains that overlap but do not coincide with Ab CDR. The number of Ag and Ab CRs per structure are overlapping and centered around 18 and 19, respectively. The CR span (CRS), a novel measure introduced in this article, is defined as the minimum contiguous amino acid sequence containing all CRs of an Ag or Ab and represents the size of a complete structural epitope or paratope, inclusive of CR and the minimum set of supporting residues required for proper conformation. The most frequent size of epitope CRS is 50–79 aa, which is similar in size to L (60–69) and H chain (70–79) CRS. The size distribution of epitope CRS analyzed in this study ranges from ∼20 to 400 aa, similar to the distribution of independent protein domain sizes reported in the literature. Together, the number of CRs and the size of the CRS demonstrate that, on average, complete structural epitopes and paratopes are equal in size to each other and similar in size to intact protein domains. Thus, independent protein domains inclusive of biologically relevant sites represent the fundamental structural unit bound by, and useful for eliciting or selecting, functional and therapeutic Abs.

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Section: Comparison Of Crr With Cdrsupporting

confidence: 84%

Antibody and Antigen Contact Residues Define Epitope and Paratope Size and Structure

Stave¹,

Lindpaintner²

2013

The Journal of Immunology

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“…Both VH and VL domains display high sequence diversity in three complementarity-determining regions (CDRs) separated by relatively conserved intervals termed framework regions [26,27]. These CDRs form loops that constitute the antigen-binding site: CDR-H3 and CDR-L3 lie generally in the center of the traditional antigen binding site and CDR-H1, CDR-H2, CDR-L1, and CDR-L2 form the outside border [28][29][30][31][32][33][34]. CDR-H3 exhibits by far the greatest sequence diversity and plays a dominant role in determining the specificity and affinity of antibody.…”

Section: Structural Aspects Of the Antigen-antibody Interfacementioning

confidence: 99%

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

2006

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HLAMatchmaker is a structurally based matching program. Each HLA antigen is viewed as a string of epitopes represented by short sequences (triplets) involving polymorphic amino acid residues in antibody-accessible positions. HLAMatchmaker determines which triplets are different between donor and recipient and this algorithm is clinically useful in determining HLA mismatch acceptability. Triplets provide however an incomplete description of the HLA epitope repertoire and expanded criteria must be used including longer sequences and polymorphic residues in discontinuous positions. Such criteria should consider the structural basis of antibody-antigen interactions including contact areas and binding energy, the essence of antigenicity.This report describes the development of a structurally defined HLA epitope repertoire based on stereochemical modeling of crystallized complexes of antibodies and different protein antigens. This analysis considered also data in the literature about contributions of amino acid residues to antigenantibody binding energy. The results have led to the concept that HLA antigens like other antigenic proteins have structural epitopes consisting of 15-22 residues that constitute the binding face with alloantibody. Each structural epitope has a functional epitope of about 2-5 residues that dominate the strength and specificity of binding with antibody. The remaining residues of a structural epitope provide supplementary interactions that increase the stability of the antigen-antibody complex. Each functional epitope has one or more non-self residues and the term "eplet" is used to describe polymorphic HLA residues within 3.0-3.5 Ångstroms of a given sequence position on the molecular surface. Many eplets represent short linear sequences identical to those referred to as triplets but others have residues in discontinuous sequence positions that cluster together on the molecular surface. Serologically defined HLA determinants correspond well to eplets. The eplet version of HLAMatchmaker represents therefore a more complete repertoire of structurally defined HLA epitopes and provides a more detailed assessment of HLA compatibility.

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“…Comparison of immature and mature B-cell subsets has shown that selection acts specifically on complementarity determining region 3 (CDR3) of the antibody heavy-chain molecule, an antigen-binding region that is a key determinant of antigen specificity (2). On average, mature B-cell subsets express antibodies that have shorter and more negatively charged CDR3s, which is the result of selection against autoreactive and polyreactive B cells (3,4).…”

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confidence: 99%

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Kaplinsky

Sun

et al. 2014

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

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Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (V H )-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in V H gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use V H genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential V H gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.immunomics | principal component analysis | development T he mature antibody repertoire is shaped by selective forces that influence B-cell survival (1). Comparison of immature and mature B-cell subsets has shown that selection acts specifically on complementarity determining region 3 (CDR3) of the antibody heavy-chain molecule, an antigen-binding region that is a key determinant of antigen specificity (2). On average, mature B-cell subsets express antibodies that have shorter and more negatively charged CDR3s, which is the result of selection against autoreactive and polyreactive B cells (3,4).Each recombined antibody heavy-chain gene is composed of a variable (V H ), diversity (D), and joining (J H ) gene segment. Because the CDR3 region spans the V H -D-J H joint, investigators have asked whether selection might favor B cells whose antibodies use specific V H , D, or J H gene segments. Selection in favor of specific gene segments during B-cell maturation might help to explain the observed maturation-associated changes in CDR3 length and charge, and might suggest a preference for "hard-wired" antigen specificities. Evidence against selection would suggest that differences in CDR3 result exclusively from the nontemplated addition and deletion of nucleotides at the V H -D and D-J H junctions, and therefore that the death of B cells with counterselected CDR3s during maturation is simply the evolutionary cost (3) of maintaining this mechanism of generating antibody diversity.Nearly two decades ago, a low-throughput sequencing study in mice suggested that specific V H gene segments were used at different frequencies by pre-B cells (in which heavy-chain recombination has been completed) and mature B cells in the spleen (5). This observation was interpreted as selection for hard-wired specificities. However, the statistical robustness of this observation was limited by the small number of recombined genes that were sequenced, and although subsequent investigations have detected differences in V H use between pre-B and upstream pro-B cells, they have failed to confirm such differences between pre-B and...

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Antibody structure and the evolution of immunoglobulin V gene segments

Cited by 107 publications

References 0 publications

Antibody and Antigen Contact Residues Define Epitope and Paratope Size and Structure

Antibody and Antigen Contact Residues Define Epitope and Paratope Size and Structure

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

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