5 research outputs found
Significant differences in physicochemical properties of human immunoglobulin kappa and lambda CDR3 regions
Antibody variable regions are composed of a heavy and a light chain, and in humans,
there are two light chain isotypes: kappa and lambda. Despite their importance in
receptor editing, the light chain is often overlooked in the antibody literature, with the
focus being on the heavy chain complementarity-determining region (CDR)-H3 region.
In this paper, we set out to investigate the physicochemical and structural differences
between human kappa and lambda light chain CDR regions. We constructed a dataset
containing over 29,000 light chain variable region sequences from IgM-transcribing,
newly formed B cells isolated from human bone marrow and peripheral blood. We also
used a published human naïve dataset to investigate the CDR-H3 properties of heavy
chains paired with kappa and lambda light chains and probed the Protein Data Bank to
investigate the structural differences between kappa and lambda antibody CDR regions.
We found that kappa and lambda light chains have very different CDR physicochemical
and structural properties, whereas the heavy chains with which they are paired do not
differ significantly. We also observed that the mean CDR3 N nucleotide addition in the
kappa, lambda, and heavy chain gene rearrangements are correlated within donors but
can differ between donors. This indicates that terminal deoxynucleotidyl transferase may
work with differing efficiencies between different people but the same efficiency in the
different classes of immunoglobulin chain within one person. We have observed large
differences in the physicochemical and structural properties of kappa and lambda light
chain CDR regions. This may reflect different roles in the humoral immune response
Promiscuous antibodies characterised by their physico-chemical properties:From sequence to structure and back
AbstractHuman B cells produce antibodies, which bind to their cognate antigen based on distinct molecular properties of the antibody CDR loop. We have analysed a set of 10 antibodies showing a clear difference in their binding properties to a panel of antigens, resulting in two subsets of antibodies with a distinct binding phenotype. We call the observed binding multiplicity ‘promiscuous’ and selected physico-chemical CDRH3 characteristics and conformational preferences may characterise these promiscuous antibodies. To classify CDRH3 physico-chemical properties playing a role in their binding properties, we used statistical analyses of the sequences annotated by Kidera factors. To characterise structure-function requirements for antigen binding multiplicity we employed Molecular Modelling and Monte Carlo based coarse-grained simulations. The ability to predict the molecular causes of promiscuous, multi-binding behaviour would greatly improve the efficiency of the therapeutic antibody discovery process