Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR*
Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR*
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DOI：
10.1074/jbc.m608425200
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发表时间：
2006-12
影响因子：
4.8
通讯作者：
M. Takeda;Shinji Ogino;R. Umemoto;M. Sakakura;M. Kajiwara;K. Sugahara;Haruko Hayasaka;M. Miyasaka;H. Terasawa;I. Shimada
中科院分区：
文献类型：
--
作者：
M. Takeda;Shinji Ogino;R. Umemoto;M. Sakakura;M. Kajiwara;K. Sugahara;Haruko Hayasaka;M. Miyasaka;H. Terasawa;I. Shimada
CD44是透明质酸(HA)的主要细胞表面受体，在其N端(残基21-178)含有一个负责HA结合的功能结构域。越来越多的证据表明，CD44胞外区(残基21-268)的蛋白降解导致肿瘤细胞的迁移和侵袭能力增强。因此，了解CD44蛋白水解性切割的机制对于理解CD44介导的肿瘤进展机制非常重要。在这里，我们介绍了CD44的HA结合结构域在其HA结合状态下的核磁共振结构。该结构由Link模块(残基32-124)和延伸叶(残基21-31和125-152)组成。有趣的是，对其非结合结构和HA结合结构的比较表明，在HA结合时，延伸叶(第143-148位)的β-链发生了重排，随后的C-末端(第153-169位)发生了结构紊乱，这与CD44HA结合区的胰酶蛋白分解研究结果一致。CD44介导的细胞迁移可能与透明质酸结合导致的C端区有序性向无序性转变有关。
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 β-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.