Conservation and diversity in the ultralong third heavy-chain complementarity-determining region of bovine antibodies

Stanfield, Robyn L.; Wilson, Ian A.; Smider, Vaughn V.

doi:10.1126/sciimmunol.aaf7962

Conservation and diversity in the ultralong third heavy-chain complementarity-determining region of bovine antibodies

Journal Article · Thu Jul 14 00:00:00 EDT 2016 · Science Immunology

DOI:https://doi.org/10.1126/sciimmunol.aaf7962· OSTI ID:1368222

Stanfield, Robyn L. ^[1]; Wilson, Ian A. ^[1]; Smider, Vaughn V. ^[2]

The Scripps Research Inst., La Jolla, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States); Fabrus Inc., San Diego, CA (United States)

Antibodies provide a broad defense against a vast array of antigens; however, the structural features that contribute to this diverse antigen recognition vary in different vertebrates. In cows, a subset of antibodies have an exceptionally long third heavy-chain complementarity-determining region (CDR H3) that is highly variable in sequence and includes multiple cysteines. These long CDR H3s (up to 69 residues) fold into a long stalk atop which sits a knob domain that is located far from the antibody surface. We have determined crystal structures of three bovine Fabs to decipher the conserved and variable features of ultralong CDR H3s that lead to diversity in antigen recognition. Despite high sequence variability, the stalks adopt a conserved β-ribbon structure, whereas the knob regions share a conserved β sheet that serves as a scaffold for two connecting loops of variable length and conformation, as well as one conserved disulfide. Variation in patterns and connectivity of the remaining disulfides contribute to the structural diversity of the knob. Finally, the unusual architecture of these ultralong bovine CDR H3s for generating diversity is unique in adaptive immune systems and may inform efforts in antibody engineering.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1368222

Journal Information:: Science Immunology, Journal Name: Science Immunology Journal Issue: 1 Vol. 1; ISSN 2470-9468

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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