Research ArticleANTIBODIES

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

See allHide authors and affiliations

Science Immunology  14 Jul 2016:
Vol. 1, Issue 1, pp. aaf7962
DOI: 10.1126/sciimmunol.aaf7962

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

“Stalk”ing the antigen

Engineers frequently look to nature for inspiration. Antibody engineers are no exception, modeling new therapeutics on molecules found in animals such as camels and cows. Indeed, 10% of bovine antibodies have unusually long heavy-chain CDR3s as part of their antigen-recognition sites. Stanfield et al. have solved crystal structures of three new bovine Fab fragments and analyzed the five known structures to show that their ultralong CDR H3s all adopt similar architectures composed of a knob domain containing a small conserved β-sheet connected by diverse disulfide-bonded loops that is separated from the antibody surface by a long conserved stalk. They propose that varying the length of the stalk and the positions and number of disulfides in the knob may help drive antibody diversity. These structural insights could be leveraged to tailor antibody-based therapeutics.


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. 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 Full Text

Stay Connected to Science Immunology