The immunoglobulin hinge (Interdomain) region

Adlersberg, Jay B.

doi:10.1007/bf02899970

Cited by 19 publications

(5 citation statements)

References 59 publications

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“…Length aside (22 aa vs 13 aa), features of the Antarctic fish hinge compared to those of the murine counterpart, e.g., richness in negatively charged residues and glycines, and a half number of cysteines (2 vs 4) potentially forming disulfide bonds, make this region certainly more flexible with less steric constraints. This could favor the proper orientation of antigen-binding sites on the Fab arms and, in turn, a high-affinity interaction of the anta-mAb (Adlersberg, 1976; Tan et al , 1990). Therefore, we attribute the increase in the apparent affinity to the mechanical mobility of the Antarctic hinge region, which can be viewed as a structural module that may contribute to local adaptive changes in flexibility.…”

Section: Discussionmentioning

confidence: 99%

“…However, the employment of the CRISPR/Cas9 system for engineering the hinge region has yet to be reported and only a few works describing hinge modifications by site-direct mutagenesis are currently available (Dell’Acqua et al , 2006; Yan et al , 2012; Ashoor et al , 2018; Suzuki et al , 2018). The hinge region is crucial in the antibody architecture, linking Fc to the Fab arms and conferring the segmental flexibility, required for the recognition and binding of a wide range of antigenic epitopes (Adlersberg, 1976; Tan et al , 1990). However, it lacks homology to any Ig constant region domain.…”

Section: Introductionmentioning

confidence: 99%

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Investigations on Antarctic fish IgM drives the generation of an engineered mAb by CRISPR/Cas9

Ametrano,

Miranda,

Moretta

et al. 2023

Preprint

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IgM is the major circulating Ig isotype in teleost fish, showing in Antarctic fish unique features such as an extraordinary long hinge region, which plays a crucial role in antibody structure and function. In this work, we describe the replacement of the hinge region of a murine monoclonal antibody (mAb) with the peculiar hinge from Antarctic fish IgM. We use the CRISPR/Cas9 system as a powerful tool for generating the engineered mAb. Then, we assessed its functionality by using an innovative plasmonic substrate based on bimetallic nanoislands (AgAuNIs). The affinity constant of the modified mAb was 2.5-fold higher than the one obtained from wild-type mAb against the specific antigen. Here, we show the suitability of the CRISPR/Cas9 method for modifying a precise region in immunoglobulin gene loci. The overall results could open a frontier in further structural modifications of mAbs for biomedical and diagnostic purposes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigations on Antarctic fish IgM drives the generation of an engineered mAb by CRISPR/Cas9

Ametrano,

Miranda,

Moretta

et al. 2023

Preprint

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“…Two-dimensional (2D) classification (Extended Data Fig. 3) of the cryo-EM data showed large-scale conformational changes at the Fab region due to the known flexibility at the mIgM hinge region [4][5][6][7] . The cryo-EM analysis produced a density map at 8.2 Å resolution (Fig.…”

Section: Reconstitution and Structure Determinationmentioning

confidence: 99%

Structural principles of B-cell antigen receptor assembly

Dong

Bartels-Burgahn

et al. 2022

Preprint

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The B-cell antigen receptor (BCR) is composed of a membrane-bound immunoglobulin (mIg) of class M, D, G, A or E for antigen recognition and a disulfide-linked heterodimer between Igα and Igβ (Igα/β, also known as CD79A and CD79B) that functions as the signalling entity. The organizing principle of BCR assembly remains elusive. Here we report the cryo-electron microscopy structures of the intact IgM class BCR at 8.2 Å resolution and its Fab-deleted form (IgM BCRΔFab) at 3.6 Å resolution. At the ectodomain (ECD), Igα and Igβ position their respective Ig folds roughly in parallel with an approximate 2-fold symmetry, which is distinct from structures of Igβ/β homodimers. Unlike previous predictions, the BCR structure displays an asymmetric arrangement, in which the Igα/β ECD heterodimer mainly uses Igα to associate with Cμ3-Cμ4 domains of one heavy chain (μHC) while leaving the other heavy chain (μHC′) empty. The transmembrane domain (TMD) helices of the two μHCs also deviate from the 2-fold symmetry of the Cμ3-Cμ4 domain dimer and form together with the TMD helices of the Igα/β heterodimer a tight 4-helix bundle. The asymmetry at the TMD helices prevents the recruitment of two Igα/β heterodimers. Surprisingly, the connecting peptides (CPs) between the ECD and TMD are braided together through striking charge complementarity, resulting in intervening of the CP of μHC in between those of Igα and Igβ and crossover of the TMD relative to ECD for the Igα/β heterodimer, to guide the TMD assembly. Interfacial analyses suggest that the IgM BCR structure we present here may represent a general organizational architecture of all BCR classes. Our studies thus provide a structural platform for understanding B-cell signalling and for designing rational therapies against BCR-mediated diseases.

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“…The two larger chains, each consisting of two domains of roughly 110 amino acids, are referred to as heavy chains. These heavy chains are connected by a flexible polypeptide chain rich in cysteine and proline known as the hinge region [76,96]. Within the hinge region, the two heavy chains are linked to each other by disulfide bonds (ranging from 2 to 11, depending on the IgG subtype) that are exposed to the surrounding solvent [97].…”

Section: Introductionmentioning

confidence: 99%

“…Preserving this structure during the modification process is crucial. The Fab regions can rotate about their axes, move in different directions at significant angles, bend, stretch, and contract to effectively engage with antigens [96,98]. Thus, the angle between the Fab regions modulates the accessibility of the antigen, and perturbations introduced during modification can reduce affinity.…”

Section: Introductionmentioning

confidence: 99%

Introduction of Carbonyl Groups into Antibodies

Gulyak,

Alferova,

Korshun

et al. 2023

Molecules

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Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody–drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl–alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.

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The immunoglobulin hinge (Interdomain) region

Cited by 19 publications

References 59 publications

Investigations on Antarctic fish IgM drives the generation of an engineered mAb by CRISPR/Cas9

Investigations on Antarctic fish IgM drives the generation of an engineered mAb by CRISPR/Cas9

Structural principles of B-cell antigen receptor assembly

Introduction of Carbonyl Groups into Antibodies

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