Revealing the Mechanisms of Protein Disorder and N-Glycosylation in CD44-Hyaluronan Binding Using Molecular Simulation.
Revealing the Mechanisms of Protein Disorder and N-Glycosylation in CD44-Hyaluronan Binding Using Molecular Simulation.
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DOI：
10.3389/fimmu.2015.00305
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发表时间：
2015
影响因子：
7.3
通讯作者：
Guvench O
中科院分区：
文献类型：
--
作者：
Guvench O
CD44 的胞外 N 端透明质酸结合结构域 (HABD) 是一个小球状结构域，赋予这种大跨膜糖蛋白透明质酸 (HA) 结合功能。当其自身重组表达时，HABD 作为球状水溶性蛋白存在，保留了结合 HA 的能力。这使得原子分辨率结构生物学实验成为可能，揭示了 HABD 的结构及其与寡聚 HA 的结合模式。此类实验还指出了 HABD 中与 HA 结合相关的有序到无序的转变。然而，目前尚不清楚这种结构转变如何参与结合，因为它发生在远离 HA 结合位点的 HABD 区域。此外，已知HABD是N-糖基化的，并且当相关的N-聚糖被唾液酸残基封端时，这种糖基化可以减少HA结合。无序蛋白质和 N-聚糖的内在灵活性使得很难应用实验结构生物学方法来探究有序到无序转变和 N-糖基化如何通过 HABD 调节 HA 结合的分子机制。我们回顾了分子动力学模拟的最新结果，这些模拟提供了对这种调制的原子分辨率机制理解，以帮助弥合现有实验结合和结构生物学数据之间的差距。这些模拟的结果包括： Tyr42 可能充当分子开关，将 HA 结合位点从低亲和力状态转换为高亲和力状态；在部分无序形式的HABD中，C端区域的碱性氨基酸可以获得足够的移动性，与结合的HA形成直接接触，进一步稳定结合；共价连接的 N-聚糖上的末端唾液酸可以与碱性氨基酸形成电荷配对氢键相互作用，否则这些氨基酸可能会与 HA 结合，从而阻止 HA 与糖基化 CD44 HABD 结合。
The extracellular N-terminal hyaluronan binding domain (HABD) of CD44 is a small globular domain that confers hyaluronan (HA) binding functionality to this large transmembrane glycoprotein. When recombinantly expressed by itself, HABD exists as a globular water-soluble protein that retains the capacity to bind HA. This has enabled atomic-resolution structural biology experiments that have revealed the structure of HABD and its binding mode with oligomeric HA. Such experiments have also pointed to an order-to-disorder transition in HABD that is associated with HA binding. However, it had remained unclear how this structural transition was involved in binding since it occurs in a region of HABD distant from the HA-binding site. Furthermore, HABD is known to be N-glycosylated, and such glycosylation can diminish HA binding when the associated N-glycans are capped with sialic acid residues. The intrinsic flexibility of disordered proteins and of N-glycans makes it difficult to apply experimental structural biology approaches to probe the molecular mechanisms of how the order-to-disorder transition and N-glycosylation can modulate HA binding by HABD. We review recent results from molecular dynamics simulations that provide atomic-resolution mechanistic understanding of such modulation to help bridge gaps between existing experimental binding and structural biology data. Findings from these simulations include: Tyr42 may function as a molecular switch that converts the HA-binding site from a low affinity to a high affinity state; in the partially disordered form of HABD, basic amino acids in the C-terminal region can gain sufficient mobility to form direct contacts with bound HA to further stabilize binding; and terminal sialic acids on covalently attached N-glycans can form charge-paired hydrogen bonding interactions with basic amino acids that could otherwise bind to HA, thereby blocking HA binding to glycosylated CD44 HABD.
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影响因子：
6.1
作者：
Dyson, H. Jane
通讯作者：
Dyson, H. Jane
影响因子：
16.8
作者：
Banerji, Suneale;Wright, Alan J.;Jackson, David G.
通讯作者：
Jackson, David G.
影响因子：
5.5
作者：
Guvench, Olgun;Hatcher, Elizabeth;Venable, Richard M.;Pastor, Richard W.;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
3
作者：
Guvench, Olgun;Greene, Shannon N.;Kamath, Ganesh;Brady, John W.;Venable, Richard M.;Pastor, Richard W.;Mackerell, Alexander D., Jr.
通讯作者：
Mackerell, Alexander D., Jr.