Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines.
The chemokine receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coreceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus. The O-linked glycans, particularly sialic acid moieties, significantly contribute to binding of the chemokine ligands. By contrast, removal of O-linked oligosaccharide exerted little effect on HIV-1 infection. Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was important for efficient beta-chemokine binding. Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of chemokines with CCR5. The resulting flexible arrays of negative charges on the CCR5 surface may allow specific, high-affinity interactions with diverse chemokine ligands. Although this is the first example of O-linked oligosaccharides and tyrosine sulfates playing a role in chemokine binding, the high density of serines, threonines and tyrosines in the N-termini of many CC chemokine receptors suggests that these posttranslational modifications may commonly contribute to chemokine binding.
Bannert
N
N
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Craig
S
S
Farzan
M
M
Sogah
D
D
Santo
N V
NV
Choe
H
H
Sodroski
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D054407:Chemokine CCL4; D006224:Cricetinae; D004285:Dogs; D015870:Gene Expression; D006031:Glycosylation; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008264:Macrophages; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism / Q000502:physiology; D013431:Sulfates / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011134:Polysaccharides; D019713:Receptors, CCR5; D013431:Sulfates; D014443:Tyrosine; D019158:N-Acetylneuraminic Acid