A family of unusual immunoglobulin superfamily genes in an invertebrate histocompatibility complex

Abstract

Invertebrate histocompatibility—also known as allorecognition—has long interested marine ecologists, population geneticists, evolutionary biologists, and immunologists, but its genetic basis remains enigmatic in most species. Here, we report the nearly complete sequence of a histocompatibility complex from the colonial cnidarian, Hydractinia symbiolongicarpus. This sequence reveals that the two known Hydractinia allorecognition genes, Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2) are part of a large family of immunoglobulin superfamily (IgSF) genes, several of which are candidates for new allodeterminants. These genes encode transmembrane proteins with domain architectures similar to cell-adhesion molecules and immune receptors. Several also contain cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) and immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Our data, which include highly accurate protein structure predictions, reveal that these proteins have V-set and I-set domains with unusual sequence signatures. This suggests the last common ancestor of cnidarians and bilaterians had distinct V-set and I-set Ig domains.

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

“…Freed from constraints in host genomes, individual domains and combinations thereof may diverge to acquire new functions, with viral genomes serving as a "testbed" of evolutionary innovation. Our study joins a growing body of work demonstrating the transformative power of structural modeling in identifying evolutionary connections 11,50,51 and informing mechanistic study 12 . The ability to detect distant homology is especially important for "hybrid" proteins such as C1, where global homology searches may be inconclusive (Figures 3A-C).…”

“…Recent advances in structural modeling such as implemented in AlphaFold2 9 have the potential to bridge this gap, and the utility of this breakthrough in identifying cryptic homology is already being appreciated. For example, ab initio modeling has been used to broadly identify pathogen mimics of host proteins 10 , to identify evolutionary connections among pathogen effectors 11 , to expand an understanding of immunoglobulin gene family evolution 12 , and to provide insight into the distant cellular origins of structural proteins found in viruses 13 . In this study, we use AlphaFold to enable searches for hidden homology in viral proteomes and test its ability to inform the mechanistic study of host-pathogen interfaces.…”