Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44.
Adhesive interactions involving CD44, the cell surface receptor for hyaluronan, underlie fundamental processes such as inflammatory leukocyte homing and tumor metastasis. Regulation of such events is critical and appears to be effected by changes in CD44 N-glycosylation that switch the receptor "on" or "off" under appropriate circumstances. How altered glycosylation influences binding of hyaluronan to the lectin-like Link module in CD44 is unclear, although evidence suggests additional flanking sequences peculiar to CD44 may be involved. Here we show using X-ray crystallography and NMR spectroscopy that these sequences form a lobular extension to the Link module, creating an enlarged HA binding domain and a formerly unidentified protein fold. Moreover, the disposition of key N-glycosylation sites reveals how specific sugar chains could alter both the affinity and avidity of CD44 HA binding. Our results provide the necessary structural framework for understanding the diverse functions of CD44 and developing novel therapeutic strategies.
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
Peter
P
Teriete
Suneale
S
Banerji
Martin
M
Noble
Charles D
CD
Blundell
Alan J
AJ
Wright
Andrew R
AR
Pickford
Edward
E
Lowe
David J
DJ
Mahoney
Markku I
MI
Tammi
Jan D
JD
Kahmann
Iain D
ID
Campbell
Anthony J
AJ
Day
David G
DG
Jackson
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012995:Solubility
D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D003545:Cysteine