Thermodynamics of T cell receptor binding to peptide–MHC: Evidence for a general mechanism of molecular scanning

Boniface, J. Jay; Reich, Ziv; Lyons, Daniel S.; Davis, Mark M.

doi:10.1073/pnas.96.20.11446

Cited by 173 publications

(131 citation statements)

References 44 publications

(55 reference statements)

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“…Surprisingly, the same ⌬H and T⌬S values were obtained by studying a different TCRpMHC pair (7). In contrast, in two other TCR-pMHC interactions analyzed in detail, the binding enthalpy was surprisingly high (⌬H ϭ Ϫ23 kcal/mol) and counterbalanced by a reduction in the entropy (T⌬S ϭ Ϫ16 kcal/mol) (8,9). The increase of the ordered state suggested that the variable loops possess conformational flexibility in the free TCR that is lost upon pMHC binding.…”

mentioning

confidence: 68%

The TCR binding site does move

Schamel¹,

Reth²

2007

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

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mentioning

confidence: 68%

The TCR binding site does move

Schamel¹,

Reth²

2007

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

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“…The structure of the CDR3 loop in intact and pMHC-bound Fab is well resolved as evident from excellent electron densities in unbiased simulated annealing omit F o ϪF c maps (supplemental Fig. 2 (10 -12) and with analyses of TCR-pMHC binding parameters (13)(14)(15). Structural plasticity of the CDR loops could allow for an adjustment of the interacting surfaces, perhaps increasing the complementarity of the pMHC/ Fab interface.…”

Section: Overall Structure Of the 25-d116-pov8-kmentioning

confidence: 94%

How a T Cell Receptor-like Antibody Recognizes Major Histocompatibility Complex-bound Peptide

Mareeva

Martı́nez-Hackert

Sykulev

2008

Journal of Biological Chemistry

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We determined the crystal structures of the T cell receptor (TCR)-like antibody 25-D1.16 Fab fragment bound to a complex of SIINFEKL peptide from ovalbumin and the H-2K b molecule. Remarkably, this antibody directly "reads" the structure of the major histocompatibility complex (MHC)-bound peptide, employing the canonical diagonal binding mode utilized by most TCRs. This is in marked contrast with another TCR-like antibody, Hyb3, bound to melanoma peptide MAGE-A1 in association with HLA-A1 MHC class I. Hyb3 assumes a non-canonical orientation over its cognate peptide-MHC and appears to recognize a conformational epitope in which the MHC contribution is dominant. We conclude that TCR-like antibodies can recognize MHC-bound peptide via two different mechanisms: one is similar to that exploited by the preponderance of TCRs and the other requires a non-canonical antibody orientation over the peptide-MHC complex.B cell receptor and its soluble analog, i.e. antibody molecules, typically recognize native antigens. However, some antibodies can recognize major histocompatibility complex (MHC) 4 -bound peptides and have been termed T cell receptor (TCR)-like antibodies. They have been derived either from large libraries containing diverse fragments encoding variable antibody regions or in the course of immunization of laboratory animals. The latter approach has proved to be less productive, suggesting that under natural conditions, TCR-like antibodies are rather rare. Because these antibodies offer attractive opportunities to track and measure particular peptide-MHC (pMHC) complexes on live cells in vitro and in vivo, a growing number of TCR-like antibodies are being developed. The molecular basis for their specificity is poorly understood, however.The TCR-like antibody 25-D1.16 has been elicited in response to immunization of mice with a whole cell bearing pOV8-K b complexes (1). This antibody has been shown to discriminate pOV8-K b from other pMHC complexes on the cell surface and has been widely used to study various aspects of processing and presentation of MHC class I (MHC-I)-restricted epitopes to cytotoxic T lymphocytes. We determined the complete primary structure of this antibody and compared its parameters of binding to pOV8-K b with those of a TCR recognizing the same ligand. This analysis led us to conclude that antibody 25-D1.16 indeed behaves like a TCR (2).Here, we report the crystal structure of 25-D1.16 Fab bound to soluble pOV8-K b protein. 25-D1.16 interacts with amino acid residues in conserved MHC positions that are believed to mediate the canonical TCR orientation of all TCR-pMHC structures studied thus far (3). Such a diagonal orientation facilitates direct contacts between both CDR3 loops of the Fab fragment and the K b -bound peptide side chains, allowing the antibody to "read" the structure of MHC-bound peptide in the same way as a TCR. Because 25-D1.16 was raised without direct contribution of CD8, which could influence TCR binding to pMHC, but still utilizes the same conserved positions to con...

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“…T cell antigen receptors have an intrinsic cross-reactivity; a single T cell antigen receptor must scan thousands of structurally similar peptidemajor histocompatibility complexes until finding the appropriate peptide-major histocompatibility complex (44). In this respect, it has been proposed that the slow association kinetics reflect conformational adaptations of the interacting surface of the T cell antigen receptor to match different peptide-major histocompatibility complexes (43,45). On the other hand, it is known that low values of k on are also typical for the interactions of pre-immune antibodies (46).…”

Section: Discussionmentioning

confidence: 99%

Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

Dimitrov

Ivanovska

Lacroix‐Desmazes

et al. 2006

Journal of Biological Chemistry

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Polyspecific antibodies represent a first line of defense against infection and regulate inflammation, properties hypothesized to rely on their ability to interact with multiple antigens. We demonstrated that IgG exposure to pro-oxidative ferrous ions or to reactive oxygen species enhances paratope flexibility and hydrophobicity, leading to expansion of the spectrum of recognized antigens, regulation of cell proliferation, and protection in experimental sepsis. We propose that ferrous ions, released from transferrin and ferritin at sites of inflammation, synergize with reactive oxygen species to modify the immunoglobulins present in the surrounding microenvironment, thus quenching pro-inflammatory signals, while facilitating neutralization of pathogens.The immune system is capable of producing a large and diverse repertoire of antibodies that can recognize a wide variety of different molecular structures and conformations. Three models for antibodyantigen interactions have been described, differing by the role of molecular flexibility. The "lock-and-key" model proposes binding between geometrically optimized partners without substantial structural alterations. In contrast, antibodies that recognize epitopes according to the "induced fit" model undergo significant structural reorganization upon binding, resulting in increased antibody-antigen complementarity (1-3). Although the first model is typical for antigen recognition by affinity-matured antibodies, the second one is intrinsic for germ line antibodies (2-5). The "conformational isomerism" model proposes that a single antibody molecule may adopt several different binding site conformations, independently of the presence of the antigen. These antibody isomers exist in equilibrium and each may recognize unrelated antigens (6 -8).An antibody molecule that relies on the use of active site flexibility for antigen binding (according to the last two models) is usually capable of accommodating a large number of structurally unrelated antigens (2, 8 -10); i.e. such an antibody is polyspecific. Polyspecific antibodies in healthy individuals represent Ͼ20% of all circulating antibodies. They play a major role in preventing pathogen dissemination in pre-immune organisms through enhanced antigen trapping (11), a property attributed to their ability to bind multiple unrelated antigens (12). Interestingly, polyspecificity of a fraction of IgG antibodies, present in all healthy individuals, can be induced in vitro by transient exposure to protein-destabilizing agents (low or high pH, high salt concentration, or chaotropic agents) (13, 14), without concomitant denaturation of the immunoglobulin molecules. Thus, in their native state, these IgGs recognize a limited panel of antigens, but exposure to the destabilizing agents leads to a dramatic expansion of the spectrum of recognized antigens. The molecular mechanism and the biological significance of this "hidden" polyspecificity remain unclear. It is also not known whether this phenomenon occurs in vivo and whether the highl...

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Thermodynamics of T cell receptor binding to peptide–MHC: Evidence for a general mechanism of molecular scanning

Cited by 173 publications

References 44 publications

The TCR binding site does move

The TCR binding site does move

How a T Cell Receptor-like Antibody Recognizes Major Histocompatibility Complex-bound Peptide

Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

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