Ligand-induced structural changes of the CD44 hyaluronan-binding domain revealed by NMR.
CD44, a major cell surface receptor for hyaluronan (HA), contains a functional domain responsible for HA binding at its N terminus (residues 21-178). Accumulating evidence indicates that proteolytic cleavage of CD44 in its extracellular region (residues 21-268) leads to enhanced tumor cell migration and invasion. Hence, understanding the mechanisms underlying the CD44 proteolytic cleavage is important for understanding the mechanism of CD44-mediated tumor progression. Here we present the NMR structure of the HA-binding domain of CD44 in its HA-bound state. The structure is composed of the Link module (residues 32-124) and an extended lobe (residues 21-31 and 125-152). Interestingly, a comparison of its unbound and HA-bound structures revealed that rearrangement of the beta-strands in the extended lobe (residues 143-148) and disorder of the structure in the following C-terminal region (residues 153-169) occurred upon HA binding, which is consistent with the results of trypsin proteolysis studies of the CD44 HA-binding domain. The order-to-disorder transition of the C-terminal region by HA binding may be involved in the CD44-mediated cell migration.
Takeda
Mitsuhiro
M
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ogino
Shinji
S
Umemoto
Ryo
R
Sakakura
Masayoshi
M
Kajiwara
Masahiro
M
Sugahara
Kazuki N
KN
Hayasaka
Haruko
H
Miyasaka
Masayuki
M
Terasawa
Hiroaki
H
Shimada
Ichio
I
D000595:Amino Acid Sequence; D002465:Cell Movement / Q000502:physiology; D018360:Crystallography, X-Ray; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D006868:Hydrolysis; D008024:Ligands; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012996:Solutions; D014357:Trypsin / Q000737:chemistry
D018960:Hyaluronan Receptors; D008024:Ligands; D012996:Solutions; D006820:Hyaluronic Acid; D014357:Trypsin