Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides.
Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides.
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两种与疾病相关的 MHC I 类蛋白与病毒和自身肽复合物的动态特征
DOI：
10.1016/j.jmb.2011.11.021
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发表时间：
2012
影响因子：
5.6
通讯作者：
Rainer A. Böckmann
中科院分区：
文献类型：
--
作者：
Daniele Narzi;Caroline M. Becker;Maria Teresa Fiorillo;Barbara Uchanskao Ziegler;Andreas Ziegler;Rainer A. Böckmann
主要组织相容性复合体（MHC）I类蛋白在细胞表面上表达，其中它们将外源和自身肽呈递给免疫系统的效应细胞。虽然已经实现了对抗原呈递的结构先决条件的理解，但对肽-MHC抗原的亚型或肽依赖性动力学特征的了解迄今为止在很大程度上是模糊的。我们采用400 ns的分子动力学模拟与两个人的MHC I类亚型作为模型系统：强直性脊柱炎相关的HLA-B HLA 27：05和非强直性脊柱炎相关的HLA-B HLA 27：09来解决这个问题。这两种蛋白质的不同之处仅在于肽结合沟（Asp 116 His）底部的微多态性。评价了病毒（pLMP 2）和三种自身肽（pVIPR、pGR和TIS）。结合槽的稳定性被认为是亚型依赖性和肽依赖性的。除TIS外，所有肽均观察到从C-和/或N-末端口袋脱离，导致两种TIS展示亚型中α1-螺旋稳定。与结合肽相关的熵的估计显示，与自身肽相比，与B 27：09相比，由B 27：05呈现的pLMP 2的熵增加。此外，α1-螺旋的柔性对于受体与B27：肽表位的结合可能是重要的，对于B B27：05，α 1-螺旋的柔性显著增强。这些计算机模拟结果表明，肽-MHC复合物的动力学性质受到结合肽和重链微多态性的影响。我们的研究结果表明，MHC I类分子的构象灵活性的背景下识别效应细胞上的受体的作用。
Major histocompatibility complex (MHC) class I proteins are expressed on the cell surface where they present foreign and self-peptides to effector cells of the immune system. While an understanding of the structural prerequisites for antigen presentation has already been achieved, insight into subtype- or peptide-dependent dynamical characteristics of a peptide–MHC antigen is so far largely obscure. We approached this problem by employing 400-ns molecular dynamics simulations with two human MHC class I subtypes as model systems: the ankylosing spondylitis-associated HLA-B∗27:05 and the non-ankylosing spondylitis-associated HLA-B∗27:09. Both proteins differ only by a micropolymorphism at the floor of the peptide binding groove (Asp116His). A viral (pLMP2) and three self-peptides (pVIPR, pGR, and TIS) were evaluated. The stability of the binding grooves was found to be both subtype dependent and peptide dependent. A detachment from the C- and/or N-terminal pockets was observed for all peptides except TIS, resulting in a stabilization of the α1-helix in both TIS-displaying subtypes. Estimates of the entropy associated with the bound peptides showed an increased entropy for pLMP2 presented by B∗27:05 as compared to B∗27:09, in contrast to the self-peptides. Additionally, the flexibility of the α1-helix that is probably important for receptor binding to the B27:peptide epitope is significantly enhanced for B∗27:05. These in silico results show that the dynamic properties of peptide–MHC complexes are affected both by the bound peptide and by micropolymorphisms of the heavy chain. Our findings suggest a role for the conformational flexibility of MHC class I molecules in the context of recognition by receptors on effector cells.
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影响因子：
2.9
作者：
Yaneva, Rakina;Springer, Sebastian;Zacharias, Martin
通讯作者：
Zacharias, Martin
疑似自身免疫病因的 HLA I 类相关疾病：HLA-B27 亚型作为模型系统
影响因子：
6.6
作者：
Uchanska-Ziegler;Fabian;Saenger;Ziegler
通讯作者：
Ziegler
影响因子：
8.6
作者：
Nurzia, Elisa;Panimolle, Francesca;Fiorillo, Maria Teresa
通讯作者：
Fiorillo, Maria Teresa
MHC I 类 α1-α2 结构域在肽结合和游离状态下的构象灵活性：分子动力学模拟研究。
影响因子：
3.4
作者：
M. Zacharias;S. Springer
通讯作者：
S. Springer
疾病相关 HLA-B27 亚型中自肽的构象二态性和分子拟态*
影响因子：
4.8
作者：
Christine Rückert;M. Fiorillo;B. Loll;R. Moretti;J. Biesiadka;W. Saenger;A. Ziegler;R. Sorrentino;B. Uchánska‐Ziegler
通讯作者：
B. Uchánska‐Ziegler