Abstract
Understanding the ancestral Ig domain's molecular structure and tracing the evolution of Ig-like proteins are fundamental components missing from our comprehension of their evolutionary trajectory and function. We have determined high-resolution structures of two Ig-like proteins from the evolutionary most ancestral phylum, Porifera. The structures reveal N-terminal Ig-like domains with an unconventional configuration of features that set them apart from canonical Ig domains. These findings prompted us to call this novel domain as Ig "Early Variable" (EV)-set. Remarkably, the EV-sets are linked to C1-set domains. To the best of our knowledge, the C1-set has not been previously reported in non-vertebrates. The IgV and IgC1 tandems and their combination into functional Ig-like receptors are part of the adaptive immune system in higher vertebrates, which allows for highly specific immune responses. By unveiling important clues into the molecular configuration of ancestral Ig domains, these findings challenge and expand our understanding of how immunity has evolved within its current landscape.