Thermodynamic and kinetic aspects of antibody evolution during the immune response to hapten

Sagawa, T.; Oda, Masayuki; Ishimura, Miyuki; Furukawa, Koji; Azuma, Takachika

doi:10.1016/s0161-5890(02)00282-1

Cited by 57 publications

(34 citation statements)

References 26 publications

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“…In contrast to our findings, a previous detailed study of a virus-neutralizing Ab using engineered mutations selected for affinity suggested that improvements in the on-rate enhanced neutralizing activity (18). Abs directed against some model Ags that have been characterized previously at a kinetic level also show an importance of the off-rate in affinity maturation caused by somatic mutations (14,15,17,37,38).…”

Section: Discussioncontrasting

confidence: 99%

Functional Maturation of the Human Antibody Response to Rotavirus

Kallewaard

McKinney

et al. 2008

The Journal of Immunology

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Infant Abs induced by viruses exhibit poor functional activity compared with those of adults. The human B cell response to rotavirus is dominated by use of the VH1–46 gene segment in both adults and infants, but only adult sequences are highly mutated. We investigated in detail the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in rotavirus-specific human Abs encoded by the immunodominant VH1–46 gene segment. Adult Abs achieved enhanced binding through naturally occurring somatic mutations in the H chain CDR2 region that conferred a markedly prolonged off-rate and a desirable increase in antiviral potency. Three-dimensional cryoelectron microscopy studies of Ag-Ab complexes revealed the mechanism of viral inhibition to be the binding of high-affinity Abs at the viral RNA release pore in the double-layer particle. These structure-function studies suggest a molecular basis for the poor quality of Abs made in infancy following virus infection or immunization.

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Section: Discussioncontrasting

confidence: 99%

Functional Maturation of the Human Antibody Response to Rotavirus

Kallewaard

McKinney

et al. 2008

The Journal of Immunology

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“…Particularly elegant studies by Wedemayer et al (8) and Patten et al (17) showed that somatic mutations throughout the Ab-combining site may preorganize the CDRs for binding. In addition, thermodynamic studies have shown that germ-line Abs may bind their targets with a more negative entropy, relative to mature Abs (22,23). Although these results are consistent with the model that affinity maturation transforms flexible receptors into more rigid receptors, the studies did not actually measure flexibility or conformational heterogeneity.…”

mentioning

confidence: 75%

Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics

Zimmermann¹,

Oakman²,

Thorpe

et al. 2006

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

116

141

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The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the challenge of quantifying protein flexibility and conformational heterogeneity as a function of evolution. Here, we report the characterization of protein heterogeneity and dynamics as a function of evolution for the antifluorescein antibody 4-4-20. Using nonlinear laser spectroscopy, surface plasmon resonance, and molecular dynamics simulations, we demonstrate that evolution localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein. This study demonstrates how protein dynamics may be tailored by evolution and has important implications for our understanding of how novel protein functions are evolved.flexibility ͉ nonlinear spectroscopy ͉ fluorscein ͉ molecular recognition

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“…Studies have demonstrated that protein flexibility may play an important role in antigen-antibody recognition and in the biological functions of proteins [22]. The high pressure and moderate temperature treatment might induce stiffness which is thought to be unfavorable for antigenantibody interactions.…”

Section: Discussionmentioning

confidence: 99%