Two-State Conformations in the Hyaluronan-Binding Domain Regulate CD44 Adhesiveness under Flow Condition
Two-State Conformations in the Hyaluronan-Binding Domain Regulate CD44 Adhesiveness under Flow Condition
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DOI：
10.1016/j.str.2010.02.010
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发表时间：
2010-05-12
期刊：
影响因子：
5.7
通讯作者：
Shimada, Ichio
中科院分区：
文献类型：
--
作者：
Ogino, Shinji;Nishida, Noritaka;Shimada, Ichio
透明质酸（HA）受体CD 44介导白细胞运输和肿瘤转移中的细胞粘附。我们以前的核磁共振（NMR）研究表明，CD 44透明质酸结合结构域（HABD）改变其构象后，HA结合，从有序（O）的部分无序（PD）的构象。在这里，我们证明了HABD经历了O和PD构象之间的平衡，在存在或不存在的HA，这解释了看似矛盾的X-射线和NMR结构的HA结合HABD。一个HABD突变体，专门采用PD构象表现出更高的HA亲和力比野生型。表达突变体CD 44的细胞的滚动效率低于表达野生型的细胞，这是由于系链频率降低和细胞解离速率缓慢。考虑到突变的CD 44，缺乏低亲和力状态，表现出受损的滚动，我们得出结论，高和低亲和力状态的HABD的共存是必不可少的CD 44介导的滚动。
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.