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Glycobiology Advance Access published online on December 23, 2003
Glycobiology, doi:10.1093/glycob/cwh039
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Submitted on October 15, 2003
Revised on November 19, 2003
Accepted on November 24, 2003

© 2003 Oxford University Press

ORIGINAL ARTICLES

A uniquely human consequence of domain-specific functional adaptation in a sialic acid-binding receptor

Justin L. Sonnenburg 1, Tasha K. Altheide 1, and Ajit Varki 1*

1 Glycobiology Research and Training Center, Departments of Medicine and Cellular & Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0687, USA

* To whom correspondence should be addressed. E-mail: avarki{at}ucsd.edu.

Abstract

Most mammalian cell surfaces display two major sialic acids (Sias), N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Humans lack Neu5Gc due to a mutation in CMP-Neu5Ac hydroxylase, which occurred after our evolutionary divergence from great apes. Here we describe an apparent consequence of human Neu5Gc loss: domain-specific functional adaptation of Siglec-9, a member of the family of sialic acid-binding receptors of innate immune cells designated the CD33-related Siglecs (CD33rSiglecs). Binding studies on recombinant human Siglec-9 show recognition of both Neu5Ac and Neu5Gc. In striking contrast, chimpanzee and gorilla Siglec-9 strongly prefer binding Neu5Gc. Simultaneous probing of multiple endogenous CD33rSiglecs on circulating blood cells of human, chimpanzee, or gorilla suggests that the binding differences observed for Siglec-9 are representative of multiple CD33rSiglecs. We conclude that Neu5Ac-binding ability of at least some human CD33rSiglecs is a derived state, which was selected for following loss of Neu5Gc in the hominid lineage. These data also indicate that endogenous Sias (rather than surface Sias of bacterial pathogens) are the functional ligands of CD33rSiglecs, and suggest that the endogenous Sia landscape is the major factor directing evolution of CD33rSiglec binding specificity. Exon-1-encoded Sia-recognizing domains of human and ape Siglec-9 share only ~93-95% amino acid identity. In contrast, the immediately adjacent intron and exon-2 have the ~98-100% identity typically observed amongst these species. Taken together, our findings suggest ongoing adaptive evolution specific to the Sia-binding domain, possibly of an episodic nature. Such domain-specific divergences should also be considered in upcoming comparisons of human and chimpanzee genomes.


sialic acid, Siglec, human evolution, domain-specific adaptation, comparative biology
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