Strong in vivo maturation compensates for structurally restricted H3 loops in antibody repertoires.

TitleStrong in vivo maturation compensates for structurally restricted H3 loops in antibody repertoires.
Publication TypeJournal Article
Year of Publication2005
AuthorsDe Genst, E., K. Silence, M. Arbabi Ghahroudi, K. Decanniere, R. Loris, J. Kinne, L. Wyns, and S. Muyldermans
JournalJ Biol Chem
Date Published2005 Apr 8
KeywordsAmino Acid Sequence, Animals, Antibody Formation, Antigens, Base Sequence, Binding Sites, Antibody, Camels, Genes, Immunoglobulin, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Muramidase, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Alignment

A central paradigm in immunology states that successful generation of high affinity antibodies necessitates an immense primary repertoire of antigen-combining sites. Much of the diversity of this repertoire is provided by varying one antigen binding loop, created by inserting randomly a D (diversity) gene out of a small pool between the V and J genes. It is therefore assumed that any particular D-encoded region surrounded by different V and J regions adopts a different conformation. We have solved the structure of two lysozyme-specific variable domains of heavy-chain antibodies isolated from two strictly unrelated dromedaries. These antibodies recombined identical D gene sequences to different V and J precursors with significant variance in their V(D)J junctions. Despite these large differences, the D-encoded loop segments adopt remarkably identical architectures, thus directing the antibodies toward identical epitopes. Furthermore, a striking convergent maturation process occurred in the V region, adapting both binders for their sub-nanomolar affinity association with lysozyme. Hence, on a structural level, humoral immunity may rely more on well developed maturation and selection systems than on the acquisition of large primary repertoires.

Alternate JournalJ. Biol. Chem.
PubMed ID15659390