Study on the Mechanism of Selective Interaction of BR3 and BCMA with BAFF and APRIL

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can activate signaling pathways by binding to specific receptors. BR3 (BAFF receptor) shows a unique selectivity for BAFF ligand, while B-cell maturation antigen (BCMA) exhibits a stronger interaction between APRIL-BCMA rather than BAFF-BCMA interaction.

The combined domains were fused with IgG1 Fc to better understand which domain affects the selective interaction of the receptor with BAFF and APRIL.

Since BR3 and BCMA both contain cysteine-rich repeat domains (CRD) with DxL motif, the binding domains of BR3 and BCMA were segmented into two parts in this study. BR3-1 (CFDLLVRHGVAC) and BCMA-1 (YFDSLLHACIPC) contained the conservative DxL motif, while BR3-2 (GLLRTPRPKPA) and BCMA-2 (QLRCSSNTPPLT) were adjacent to the CRDs yet still joined with BR3-1 and BCMA-1. Affinity between all possible combinations was then tested.

The affinity of BR3-1-BCMA-2-Fc and BR3-1-BR3-2-Fc for BAFF was higher than BCMA-1-BR3-2-Fc and BCMA-1-BCMA-2-Fc. Moreover, BR3-1-BCMA-2-Fc and BCMA-1-BCMA- 2-Fc had affinity for APRIL, while BR3-1-BR3-2-Fc and BCMA-1-BR3-2-Fc hardly interacted with APRIL.

BR3-1 region played a key role for interaction with BAFF, while BCMA-1 region exhibited weaker binding with BAFF. BCMA-2 region having an α-helix might contribute towards selectivity of APRIL-BCMA binding and BR3-2 rigid region had deleterious effects on the APRIL-BR3 interaction. These results provide comprehensive insights of the mechanism of selective interactions, and may promote specific antagonist design in the future.