The link module from ovulation- and inflammation-associated protein TSG-6 changes conformation on hyaluronan binding.
The solution structure of the Link module from human TSG-6, a hyaladherin with important roles in inflammation and ovulation, has been determined in both its free and hyaluronan-bound conformations. This reveals a well defined hyaluronan-binding groove on one face of the Link module that is closed in the absence of ligand. The groove is lined with amino acids that have been implicated in mediating the interaction with hyaluronan, including two tyrosine residues that appear to form essential intermolecular hydrogen bonds and two basic residues capable of supporting ionic interactions. This is the first structure of a non-enzymic hyaladherin in its active state, and identifies a ligand-induced conformational change that is likely to be conserved across the Link module superfamily. NMR and isothermal titration calorimetry experiments with defined oligosaccharides have allowed us to infer the minimum length of hyaluronan that can be accommodated within the binding site and its polarity in the groove; these data have been used to generate a model of the complex formed between the Link module and a hyaluronan octasaccharide.
Blundell
Charles D
CD
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, United Kingdom.
Mahoney
David J
DJ
Almond
Andrew
A
DeAngelis
Paul L
PL
Kahmann
Jan D
JD
Teriete
Peter
P
Pickford
Andrew R
AR
Campbell
Iain D
ID
Day
Anthony J
AJ
D000595:Amino Acid Sequence; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D004926:Escherichia coli / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D006860:Hydrogen Bonding; D007249:Inflammation / Q000503:physiopathology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010060:Ovulation / Q000502:physiology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D015815:Cell Adhesion Molecules; D006820:Hyaluronic Acid