title: Reshaping antibody diversity.
abstract: Some species mount a robust antibody response despite having limited genome-encoded combinatorial diversity potential. Cows are unusual in having exceptionally long CDR H3 loops and few V regions, but the mechanism for creating diversity is not understood. Deep sequencing reveals that ultralong CDR H3s contain a remarkable complexity of cysteines, suggesting that disulfide-bonded minidomains may arise during repertoire development. Indeed, crystal structures of two cow antibodies reveal that these CDR H3s form a very unusual architecture composed of a β strand "stalk" that supports a structurally diverse, disulfide-bonded "knob" domain. Diversity arises from somatic hypermutation of an ultralong DH with a severe codon bias toward mutation to cysteine. These unusual antibodies can be elicited to recognize defined antigens through the knob domain. Thus, the bovine immune system produces an antibody repertoire composed of ultralong CDR H3s that fold into a diversity of minidomains generated through combinations of somatically generated disulfides.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Damian C
authors.initials: DC
authors.lastname: Ekiert
authors.forename: Insha
authors.initials: I
authors.lastname: Ahmad
authors.forename: Wenli
authors.initials: W
authors.lastname: Yu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Omar
authors.initials: O
authors.lastname: Bazirgan
authors.forename: Ali
authors.initials: A
authors.lastname: Torkamani
authors.forename: Terje
authors.initials: T
authors.lastname: Raudsepp
authors.forename: Waithaka
authors.initials: W
authors.lastname: Mwangi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Criscitiello
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Vaughn V
authors.initials: VV
authors.lastname: Smider
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000916:Antibody Diversity; D002417:Cattle / Q000276:immunology*; D022801:Complementarity Determining Regions; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000032:analysis / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics*; D007075:Immunoglobulin M / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D003545:Cysteine