Ig or Not Ig? That Is the Question: The Nucleating Supersecondary Structure of the Ig-Fold and the Extended Ig Universe.

Observing the omnipresence of the Ig-fold in all domains of life, one may wonder why this fold among all is such a wunderkind of evolution. Culminating in vertebrates, it enables a myriad of functions at the heart of the immune, nervous, vascular, and muscular systems. We suggest the Ig-fold resilience lies in the robust folding of a core supersecondary structure (SSS) that can accommodate a myriad of topological variations. In this chapter, we focus on the core supersecondary structure common to all topostructural variants of the Ig-fold and will see that this pattern can also be found in other β-sandwich folds. It represents a highly resilient central SSS that accommodates a very high plasticity observed among β-sandwiches. We have recently developed a universal numbering system to identify and annotate Ig-domains, Ig-like domains, and what we now call Ig-extended domains, i.e., β-sandwiches that contain and extend the Ig-fold topology (to be published). A universal numbering scheme, common to all topological and structural variants of any domain sharing the Ig-fold, allows a direct comparison of any Ig, Ig-like, and Ig-extended domain in sequence, topology, and structure. This can therefore help understand the robust patterns in Ig-folding and interactions with other Ig or non-Ig proteins, as well as help trace evolutionary patterns of immunoglobulin domains. The universal numbering scheme, called IgStrand, is now at the heart of an algorithm that can label secondary structure elements of the Ig-fold for any topological variant. It is implemented in the open-source web-based iCn3D program from NCBI (Wang, Youkharibache, Zhang, Lanczycki, Geer, Madej, Phan, Ward, Lu, Marchler, Bioinformatics 36:131-135, 2020). Interestingly, that algorithm captures SSS homologies across a very large spectrum of β-sandwiches, and one can envision classifying numerous such sandwiches as "Ig-extended" domains and their variable topological arrangements. In this chapter, we go through examples of Ig, Ig-like, and Ig-extended domains as in a journey through cells: in the cell nucleus, in the cytoplasm, or on extracellular regions of cell surface receptors, and in viruses.