Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions.
| Autor: | Jenkins GW; Applied Biomedical Science Institute, San Diego, CA., Safonova Y; Computer Science and Engineering Department, University of California, San Diego, La Jolla, CA.; Department of Computer Science, Johns Hopkins University, Baltimore, MD; and., Smider VV; Applied Biomedical Science Institute, San Diego, CA.; Department of Molecular Medicine, Scripps Research, La Jolla, CA. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Dec 01; Vol. 209 (11), pp. 2141-2148. |
| DOI: | 10.4049/jimmunol.2200455 |
| Abstrakt: | Ab "ultralong" third H chain complementarity-determining regions (CDR H3) appear unique to bovine Abs and may enable binding to difficult epitopes that shorter CDR H3 regions cannot easily access. Diversity is concentrated in the "knob" domain of the CDR H3, which is encoded by the DH gene segment and sits atop a β-ribbon "stalk" that protrudes far from the Ab surface. Knob region cysteine content is quite diverse in terms of total number of cysteines, sequence position, and disulfide bond pattern formation. We investigated the role of germline cysteines in production of a diverse CDR H3 structural repertoire. The relationship between DH polymorphisms and deletions relative to germline at the nucleotide level, as well as diversity in cysteine and disulfide bond content at the structural level, was ascertained. Structural diversity is formed through (1) DH polymorphisms with altered cysteine positions, (2) DH deletions, and (3) new cysteines that arise through somatic hypermutation that form new, unique disulfide bonds to alter the knob structure. Thus, a combination of mechanisms at both the germline and somatic immunogenetic levels results in diversity in knob region cysteine content, contributing to remarkable complexity in knob region disulfide patterns, loops, and Ag binding surface. (Copyright © 2022 by The American Association of Immunologists, Inc.) |
| Databáze: | MEDLINE |
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