Unusual traits shape the architecture of the Ig ancestor molecule

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 elucidated the molecular structures of two Ig-like proteins from the evolutionary most ancestral phylum, Porifera , revealing previously unidentified Ig-domain features that highlight the concomitant presence of a novel Ig “Early Variable” (EV)-set in tandem with a C1-set domain. The latter, to our knowledge, has never been reported before in non-vertebrates. The IgV and IgC1 sets 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. These observations in the ancient Porifera phylum could indicate the presence of primitive forms of adaptive immunity or a foundational immune strategy that has been conserved through evolution. 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.