title: Two-state conformations in the hyaluronan-binding domain regulate CD44 adhesiveness under flow condition.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ogino
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nishida
authors.forename: Ryo
authors.initials: R
authors.lastname: Umemoto
authors.forename: Miho
authors.initials: M
authors.lastname: Suzuki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Terasawa
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Haruko
authors.initials: H
authors.lastname: Hayasaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Ichio
authors.initials: I
authors.lastname: Shimada
mesh_terms: 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
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid