Domain motions of hyaluronan lyase underlying processive hyaluronan translocation
Domain motions of hyaluronan lyase underlying processive hyaluronan translocation
复制标题
DOI：
10.1002/prot.22316
复制
发表时间：
2009-07-01
影响因子：
2.9
通讯作者：
de Groot, Bert L.
中科院分区：
文献类型：
--
作者：
Joshi, Harshad V.;Jedrzejas, Mark J.;de Groot, Bert L.
透明质酸裂解酶 (Hyal) 是一种存在于许多细菌生物体（包括链球菌属成员）中的表面酶。 Hyal 链球菌主要降解细胞外基质的透明质酸底物 (HA)。这种降解似乎促进了这种细菌在整个宿主组织中的传播。与其他底物（非硫酸化软骨素或某些硫酸软骨素）的纯粹内溶降解不同，Hyal 对 HA 的降解是在初始内溶切割后通过每次一种二糖的持续外切裂解来进行的。提出了对肺炎链球菌 Hyal 的分子动力学 (MD) 研究，解决了酶的分子作用机制以及结构域运动对处理功能的作用。对这种酶对不同长度的 HA 底物的作用进行广泛的亚微秒 MD 模拟分析，以及 Hyal 的域动力学与 HA 底物的易位之间的联系，揭示了 Hyal 的打开/关闭和扭转域运动与持续的 HA 降解密切相关。强制模拟证实了这一发现，因为 SpnHyal 中的域运动被发现是由强制底物易位引起的。这些结果建立了 Hyal 灵活性和底物易位之间的动态相互作用，并提供了对 Hyal 加工机制的深入了解。
Hyaluronan lyase (Hyal) is a surface enzyme occurring in many bacterial organisms including members of Streptococcus species. Streptococcal Hyal primarily degrades hyaluronan-substrate (HA) of the extracellular matrix. This degradation appears to facilitate the spread of this bacterium throughout host tissues. Unlike purely endolytic degradation of its other substrates, unsulfated chondroitin or some chondroitin sulfates, the degradation of HA by Hyal proceeds by processive exolytic cleavage of one disaccharide at a time following an initial endolytic cut. Molecular dynamics (MD) studies of Hyal from Streptococcus pneumoniae are presented that address the enzyme's molecular mechanism of action and the role of domain motions for processive functionality. The analysis of extensive sub-microsecond MD simulations of this enzyme action on HA-substrates of different lengths and the connection between the domain dynamics of Hyal and the translocation of the HA-substrate reveals that opening/closing and twisting domain motions of the Hyal are intimately linked to processive HA degradation. Enforced simulations confirmed this finding as the domain motions in SpnHyal were found to be induced by enforced substrate translocation. These results establish the dynamic interplay between Hyal flexibility and substrate translocation and provide insight into the processive mechanism of Hyal.