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Conformational Heterogeneity in Antibody-Protein Antigen Recognition IMPLICATIONS FOR HIGH AFFINITY PROTEIN COMPLEX FORMATION
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SYSNO ASEP 0431518 Document Type J - Journal Article R&D Document Type The record was not marked in the RIV Subsidiary J Článek ve WOS Title Conformational Heterogeneity in Antibody-Protein Antigen Recognition IMPLICATIONS FOR HIGH AFFINITY PROTEIN COMPLEX FORMATION Author(s) Addis, P. W. (GB)
Hall, c. J. (GB)
Bruton, S. (GB)
Veverka, Václav (UOCHB-X) RID, ORCID
Wilkinson, I. C. (GB)
Muskett, F. W. (GB)
Renshaw, P. S. (GB)
Prosser, C. E. (GB)
Carrington, B. (GB)
Lawson, A. D. G. (GB)
Griffin, R. (GB)
Taylor, R. J. (GB)
Waters, L. C. (GB)
Henry, A. J. (GB)
Carr, M. D. (GB)Number of authors 15 Source Title Journal of Biological Chemistry. - : Elsevier - ISSN 0021-9258
Roč. 289, č. 10 (2014), s. 7200-7210Number of pages 11 s. Language eng - English Country US - United States Keywords NMR ; antibody ; protein-protein interaction ; protein conformation Subject RIV CE - Biochemistry Institutional support UOCHB-X - RVO:61388963 UT WOS 000332389400078 EID SCOPUS 84896758400 DOI 10.1074/jbc.M113.492215 Annotation Specific, high affinity protein-protein interactions lie at the heart of many essential biological processes, including the recognition of an apparently limitless range of foreign proteins by natural antibodies, which has been exploited to develop therapeutic antibodies. To mediate biological processes, high affinity protein complexes need to form on appropriate, relatively rapid timescales, which presents a challenge for the productive engagement of complexes with large and complex contact surfaces (approximate to 600-1800 (2)). We have obtained comprehensive backbone NMR assignments for two distinct, high affinity antibody fragments (single chain variable and antigen-binding (Fab) fragments), which recognize the structurally diverse cytokines interleukin-1 (IL-1, -sheet) and interleukin-6 (IL-6, -helical). NMR studies have revealed that the hearts of the antigen binding sites in both free anti-IL-1 Fab and anti-IL-6 single chain variable exist in multiple conformations, which interconvert on a timescale comparable with the rates of antibody-antigen complex formation. In addition, we have identified a conserved antigen binding-induced change in the orientation of the two variable domains. The observed conformational heterogeneity and slow dynamics at protein antigen binding sites appears to be a conserved feature of many high affinity protein-protein interfaces structurally characterized by NMR, suggesting an essential role in protein complex formation. We propose that this behavior may reflect a soft capture, protein-protein docking mechanism, facilitating formation of high affinity protein complexes on a timescale consistent with biological processes. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2015
Number of the records: 1