Two-state conformations in the hyaluronan-binding domain regulate CD44 adhesiveness under flow condition.
The hyaluronan (HA) receptor CD44 mediates cell adhesion in leukocyte trafficking and tumor metastasis. Our previous nuclear magnetic resonance (NMR) studies revealed that the CD44 hyaluronan-binding domain (HABD) alters its conformation upon HA binding, from the ordered (O) to the partially disordered (PD) conformation. Here, we demonstrate that the HABD undergoes an equilibrium between the O and PD conformations, in either the presence or absence of HA, which explains the seemingly contradictory X-ray and NMR structures of the HA-bound HABD. An HABD mutant that exclusively adopts the PD conformation displayed a higher HA affinity than the wild-type. Rolling of the cells expressing the mutant CD44 was less efficient than those expressing the wild-type, due to the decreased tether frequency and the slow cellular off rate. Considering that the mutant CD44, devoid of the low-affinity state, exhibited impaired rolling, we conclude that the coexistence of the high- and low-affinity states of the HABD is essential for the CD44-mediated rolling.
Ogino
Shinji
S
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Nishida
Noritaka
N
Umemoto
Ryo
R
Suzuki
Miho
M
Takeda
Mitsuhiro
M
Terasawa
Hiroaki
H
Kitayama
Joji
J
Matsumoto
Masanori
M
Hayasaka
Haruko
H
Miyasaka
Masayuki
M
Shimada
Ichio
I
D055592:Biophysical Phenomena; D002448:Cell Adhesion; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D055585:Physical Phenomena; D014965:X-Rays
D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid