Abstract
The Ig fold has had a remarkable success in vertebrate evolution, with a presence in over 2% of human genes. The Ig fold is not just the elementary structural domain of antibodies and TCRs, it is also at the heart of a staggering 30% of immunologic cell surface receptors, making it a major orchestrator of cell–cell interactions. While BCRs, TCRs, and numerous Ig-based cell surface receptors form homo- or heterodimers on the same cell surface (in cis), many of them interface as ligand-receptors (checkpoints) on interacting cells (in trans) through their Ig domains. New Ig-Ig interfaces are still being discovered between Ig-based cell surface receptors, even in well-known families such as B7. What is largely ignored, however, is that the Ig fold itself is pseudosymmetric, a property that makes the Ig domain a versatile self-associative 3D structure and may, in part, explain its success in evolution, especially through its ability to bind in cis or in trans in the context of cell surface receptor–ligand interactions. In this paper, we review the Ig domains’ tertiary and quaternary pseudosymmetries, with particular attention to the newly identified double Ig fold in the solved CD19 molecular structure to highlight the underlying fundamental folding elements of Ig domains, i.e., Ig protodomains. This pseudosymmetric property of Ig domains gives us a decoding frame of reference to understand the fold, relate all Ig domain forms, single or double, and suggest new protein engineering avenues.
Highlights
We focus on the tertiary symmetries across all topological variants of Ig domains and dissect the formation of a new tertiary fold—the double Ig domain observed in CD19, which confirms the protodomain hypothesis
The immunoglobulin fold is at the heart of a very large number of cell surface proteins of the immune system, beyond immunoglobulins themselves, and we have seen that the Ig fold exhibits tertiary symmetry as well as quaternary symmetry, as in CD8 or VL-VL homodimers or the very well-known antibody variable domain association—VH-VL
If we look at IgV-IgV quaternary interfaces in cell surface receptor/ligands beyond PD-1/PD-L1, such as in CD28 and/or B7 receptors, they exhibit a wide variety of interfaces, many, use their GFCC’ sheets to interact, even if they depart from the canonical interface used by VH-VL domains in antibodies or by CD8 dimers
Summary
20% of known protein folds/domains are pseudosymmetric [1], and that in each structural class [2], the most diversified fold exhibits pseudosymmetry, suggesting a link between symmetry and evolution. Two classes of folds show a higher proportion of pseudosymmetric domains: membrane proteins, with, for example, GPCRs [3], and beta folds, chief among them the Ig fold [4]. B-cell, and T-cell receptors and coreceptors, the Ig domain is present in a very large number of T-cell costimulatory and coinhibitory checkpoints that regulate adaptive immunity with, in particular, the CD28 family of receptors containing the well-known CTLA-4 and PD-1 receptors and their ligands from the B-7 family [8,9,10]. The Ig fold accounts for a staggering 30% of cell surface receptors’ extracellular domains [7], making it a major orchestrator of cell–cell interactions
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