Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions

Author:

Jenkins Gabrielle Warner1,Safonova Yana23,Smider Vaughn V.14ORCID

Affiliation:

1. *Applied Biomedical Science Institute, San Diego, CA;

2. †Computer Science and Engineering Department, University of California, San Diego, La Jolla, CA;

3. ‡Department of Computer Science, Johns Hopkins University, Baltimore, MD; and

4. §Department of Molecular Medicine, Scripps Research, La Jolla, CA

Abstract

Abstract 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.

Funder

HHS | NIH | National Institute of General Medical Sciences

HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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