Sialic Acid Recognition by Siglecs

Humans lack the common mammalian cell surface sialic acid N-glycolylneuraminic acid (Neu5Gc), due to a mutation in CMP-Neu5Ac hydroxylase, which occurred after our evolutionary divergence from great apes. One apparent consequence of human Neu5Gc loss is a domain-specific functional adaptation of Siglec-9, a major member of the family of sialic acid-binding receptors of immune cells that are designated the CD33-related Siglecs (CD33rSiglecs). While recombinant human Siglec-9 showed recognition of both Neu5Ac and Neu5Gc, chimpanzee and gorilla Siglec-9 were found to strongly prefer to bind to Neu5Gc. Probing of multiple endogenous CD33rSiglecs on circulating blood cells suggest that the binding differences observed for Siglec-9 are representative of the other CD33rSiglecs. Thus, the Neu5Ac-binding ability of at least some of the human CD33rSiglecs appears to be a derived state, which was apparently selected for following loss of Neu5Gc in the hominid lineage. In keeping with this, findings suggested ongoing adaptive evolution specific to the sialic acid-binding domain of Siglec-9.