Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

PLoS Pathogens

H. Benjamin Larman¹  Roland K. Strong¹  Kevin Larimore²  Philip D. Greenberg²  Stephen J. Elledge³  Kathryn A. K. Finton⁴  James Jaffe⁴  Della Friend⁴  Margaret A. Holmes⁴  Mesfin Gewe⁴  Leonidas Stamatatos⁵  Andrew Stuart⁶ 

[1] Department of Genetics, Harvard University Medical School, and Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, United States of America;Department of Immunology, University of Washington, Seattle, Washington, United States of America;Department of Medicine, University of Washington, Seattle, Washington, United States of America;Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Program in Immunology, Cancer Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Seattle Biomedical Research Institute, Seattle, Washington, United States of America

关键词: DNA-binding proteins;    Crystal structure;    Morphogenesis;    Antigens;    Binding analysis;    Antibodies;    Somatic mutation;    Protein domains;   

DOI  :  10.1371/journal.ppat.1004403

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies.

【 授权许可】

CC BY