Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Nair, D.T.; Singh, Kavita; Siddiqui, Zaved; Nayak, Bishnu P.; Rao, Kanury V. S.

doi:10.4049/jimmunol.168.5.2371

Cited by 87 publications

(56 citation statements)

References 48 publications

(51 reference statements)

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“…The PS1 epitope was driven to a common conformational state and the CDRs of each of the independent mature mAbs against this epitope adopted identical conformations while binding to it (31). Thus, contrary to the broad conformational repertoire of the primary Abs observed in the current study, that of the mature Abs was conserved during Ag binding (31)(32)(33)(34).…”

Section: Discussioncontrasting

confidence: 45%

Adjustable Locks and Flexible Keys: Plasticity of Epitope–Paratope Interactions in Germline Antibodies

Khan

Salunke

2014

The Journal of Immunology

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Ag recognition by independent primary Abs against a small flexible Ag with overlapping epitopes was analyzed to address the determinants of Ag specificity during the initial encounter. Crystal structures of two distinct dodecapeptide Ags, GDPRPSYISHLL and PPYPAWHAPGNI, in complex with the germline mAb 36-65 were determined and compared with the structures of the same Ags bound to another independent germline mAb, BBE6.12H3. For each peptide Ag, the two germline mAbs recognized overlapping epitopes, but in different topologies. The peptide structures differed, and the two paratopes attained discrete conformations, leading to different surface topologies, in a mode that can be described as adjustable locks and flexible keys. This is in contrast to mature mAbs, in which conformational convergence of different paratopes while binding to a common epitope in a similar conformation has been reported. These results suggest that the primary immune receptor repertoire is highly versatile as compared with its mature counterpart. Germline and mature mAbs adopt distinct mechanisms for recognizing a flexible epitope. Whereas conservation of conformational repertoire is a key characteristic of mature mAbs achieved through affinity maturation, the germline mAbs, at the initial stages of Ag encounter, maintain substantial plasticity, accommodating a broad specificity repertoire.

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Section: Discussioncontrasting

confidence: 45%

Adjustable Locks and Flexible Keys: Plasticity of Epitope–Paratope Interactions in Germline Antibodies

Khan

Salunke

2014

The Journal of Immunology

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“…Partial obstruction of TSAb binding to its epitope(s) may also explain the mechanism by which these autoantibodies can activate the TSHR. The binding interaction between an Ab and its binding site is remarkably flexible, or "plastic" (42). Such plasticity may be more marked when an epitope is partially obstructed and could thereby have a torsional effect on the TSHR ectodomain.…”

Section: Discussionmentioning

confidence: 99%

Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor

Chazenbalk

Pichurin²,

Chen³

et al. 2002

J. Clin. Invest.

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Graves disease is directly caused by thyroid-stimulating autoantibodies (TSAb’s) that activate the thyrotropin receptor (TSHR). We observed upon flow cytometry using intact cells that a mouse mAb (3BD10) recognized the TSHR ectodomain with a glycosidylphosphatidylinositol (ECD-GPI) anchor approximately tenfold better than the same ectodomain on the wild-type TSHR, despite the far higher level of expression of the latter. The 3BD10 epitope contains the N-terminal cysteine cluster critical for TSAb action. Consequently, we hypothesized and confirmed that TSAb (but not thyrotropin-blocking autoantibodies [TBAb’s]) also poorly recognize the wild-type TSHR relative to the ECD-GPI. Despite poor recognition by TSAb of the holoreceptor, soluble TSHR A subunits (known to be shed from surface TSHR) fully neutralized autoantibody-binding activity. These data indicate that the epitope(s) for TSAb’s, but not for TBAb’s, are partially sterically hindered on the holoreceptor by the plasma membrane, the serpentine region of the TSHR, or by TSHR dimerization. However, the TSAb epitope on the soluble A subunit is freely accessible. This observation, as well as other evidence, supports the concept that A subunit shedding either initiates or amplifies the autoimmune response to the TSHR, thereby causing Graves disease in genetically susceptible individuals

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“…Whether the reduced b12 affinity for mutant mCHO*-GDMR translates into difficulties in using this mutant to elicit b12-like antibodies is unpredictable. However, one of the remarkable features of the humoral immune response is its plasticity (50,51,58,69,113). This flexibility, which is represented by the variable regions of immunoglobulins, in particular within the paratope, may enable antibodies with disparate sequences to recognize gp120 equivalent to b12 and neutralize viral isolates with comparable efficacy.…”

Section: Fig 8 Reactivity Of Hivig (Open Symbols)mentioning

confidence: 99%

Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design

Pantophlet¹,

Wilson

Burton³

2003

J Virol

122

109

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The ability to induce broadly neutralizing antibodies should be a key component of any forthcoming vaccine against human immunodeficiency virus type 1. One potential vaccine candidate, monomeric gp120, has generally failed to elicit such antibodies. We postulated that gp120 might be a better immunogen if it could be engineered to preferentially bind known broadly neutralizing antibodies. In a first study, we found that four alanine substitutions on the perimeter of the so-

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Epitope Recognition by Diverse Antibodies Suggests Conformational Convergence in an Antibody Response

Cited by 87 publications

References 48 publications

Adjustable Locks and Flexible Keys: Plasticity of Epitope–Paratope Interactions in Germline Antibodies

Adjustable Locks and Flexible Keys: Plasticity of Epitope–Paratope Interactions in Germline Antibodies

Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor

Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design

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