T-cell co-stimulation through CD28/CTLA4:B7-1/B7-2 axis is one of the extensively studied pathways that resulted in the discovery of several FDA-approved drugs for autoimmunity and cancer. However, many aspects of the signaling mechanism remain elusive, including oligomeric association and clustering of B7-2 on the cell surface. Here, we describe the structure of the IgV domain of B7-2 and its cryptic association into 1D arrays that appear to represent the pre-signaling state of B7-2 on the cell membrane. Super-resolution microscopy experiments on heterologous cells expressing B7-2 and B7-1 suggest, B7-2 form relatively elongated and larger clusters compared to B7-1. The sequence and structural comparison of other B7 family members, B7-1:CTLA4 and B7-2:CTLA-4 complex structures, support our view that the observed B7-2 1D zipper array is physiologically important. This observed 1D zipper-like array also provides an explanation for its clustering, and upright orientation on the cell surface, and avoidance of spurious signaling.
Keywords: B7-2 structure; immune checkpoint blockade; immune receptors; protein clustering.
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