Journal Club: The Origin of CDR H3 Structural Diversity

Antibody binding site is broadly composed of the six hypervariable loops, the CDRs. There are three loops on the antibody light chain (L1, L2 and L3) and three loops on the antibody heavy chain (H1, H2 and H3).

Out of the six loops, five appear to adopt a constrained set of structural conformations (L1, L2, L3, H1 and H2). The conformations of H3 appear much less constrained, which was suggested to be the result of its higher relative importance in antigen recognition (however it is not a necessary condition). The only observations to date about the shapes of CDR-H3 is the existence of the extended and kinked conformations of its anchor.

The function of the kink was investigated recently by Weitzner et al. Here, the authors contrasted the geometry found in the antibody CDR-H3 loops to a set of 15k non-antibody polypeptides. They found that even though the extended conformation appears to be more favorable, the kinked one can also be found in many cases, particularly in the PDZ domains.

Weitzner et al. find that the extended conformation is much more common in non-antibody loops. However, the kinked conformation, even though less frequent is not outright rare. The situation is the opposite in antibodies where the majority of H3 conformations are kinked rather than extended.

The authors contrasted the sequence patterns of kinked antibody loops and kinked non-antibody loops and did not find anything predictive of the kinked conformation — suggesting that the effect might be non-local. Nonetheless, the secondary structure pattern of the kinked H3 and the kinked non-antibody loops appears similar.

Even though there might be no sequence-kink link, the authors indicate how their findings might improve H3 structure prediction. They demonstrate that admixing the kinked non-antibody loops into a template dataset for an H3 modeling software might provide more relevant templates.

In conclusion, the main message of the paper (selon moi) is putting forward of the hypothesis as to the role of the H3 kink. Since the kink is much more prevalent in H3 than in non-antibody proteins, there is a strong suggestion that there might be a special role for it. The authors suggest that the kinked conformation allows for more structural diversity, that would otherwise be restricted in the more rigid beta-stranded extended conformation. Thus, antibodies might have opted for a system wherein, they do not need to add dramatic mutations to their H3 in order to get more structural flexibility.

 

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