A novel hypothesis regarding the evolutionary origins of the immunoglobulin fold

The recent cloning of two cDNAs (Clone 1 and Clone 5) that encode novel hypothetical proteins, combining an N-terminal Ig kappa-like domain with features that occur in microfibril-associated glycoproteins (MAGPs) and fibrinogen, raises the question of whether the Ig fold may have originated in association with functions that may be more primitive than soluble immunity. Pairwise alignments were performed to compare similarities of fibrinogen-beta, Clone 1 and an Ig kappa sequence. Clone 1 had two regions in its Ig domain with > 50% similarity to fibrinogen, while Ig kappa was virtually non-homologous to fibrinogen. This result suggests that Clone 1 is closer to their common ancestor. A neighbour-joining tree was computed, and it supported this interpretation. Three-dimensional modelling of the most highly conserved sequence revealed two antiparallel beta strands connected by a helix. These observations suggest that the ancestral gene for the immunoglobulin superfamily may have originated as a primitive sandwich-like fold, possibly used in matrix/cell communications.