Cooperativity during the formation of peptide/MHC class II complexes
Cooperativity during the formation of peptide/MHC class II complexes
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DOI：
10.1021/bi048675s
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发表时间：
2005-04-19
期刊：
影响因子：
2.9
通讯作者：
Gorski, J
中科院分区：
文献类型：
--
作者：
Anderson, MW;Gorski, J
为了产生有效的免疫应答，II类主要组织相容性复合体分子（MHCII）必须呈现多种肽配体以供T淋巴细胞识别。多肽/MHCII复合物通过在MHCII蛋白上疏水锚定肽侧链和在多肽主链上形成氢键来稳定。许多当前的多肽/MHCII关联模型假设主要MHCII口袋和肽中相应侧链之间的相互作用是附加的和独立的贡献。然而，在结合过程中，肽和MHCII都发生了显著的构象重排。因此，我们假设肽与MHCII的结合可以被视为一个折叠过程，在这个过程中，两个分子合作产生最终的构象。为了直接验证这一假设，我们采用了一系列诱变策略来研究人类MHCII HLA-DR1与流感血凝素衍生肽相互作用的协同性。预测干扰氢键形成的肽或HLA-DR1的取代对络合物的稳定性和亲和力表现出协同效应。提供疏水接触的肽侧链的替代也有助于合作效应，这表明所有能量源在折叠过程中都起作用。我们提出，整个肽结合槽的协同性反映了MHCII分子的片段在肽周围折叠成螺旋，同时肽折叠成脯氨酸螺旋。讨论了协同性对肽/MHCII结构和表位选择的影响。
To generate an effective immune response, class II major histocompatibility complex molecules (MHCII) must present a diverse array of peptide ligands for recognition by T lymphocytes. Peptide/MHCII complexes are stabilized by hydrophobic anchoring of peptide side chains to pockets in the MHCII protein and the formation of hydrogen bonds to the peptide backbone. Many current models of peptide/MHCII association assume an additive and independent contribution of the interactions between major MHCII pockets and corresponding side chains in the peptide. However, significant conformational rearrangements occur in both the peptide and MHCII during binding. Therefore, we hypothesize that peptide binding to MHCII could be viewed as a folding process in which both molecules cooperate to produce the final conformation. To directly test this hypothesis, we adapt a serial mutagenesis strategy to study cooperativity in the interaction of the human MHCII HLA-DR1 and a peptide derived from influenza hemagglutinin. Substitutions in either the peptide or HLA-DR1 that are predicted to interfere with hydrogen bond formation show cooperative effects on complex stability and affinity. Substitution of a peptide side chain that provides a hydrophobic contact also contributes to the cooperative effect, suggesting a role for all energetic sources in the folding process. We propose that cooperativity throughout the peptide-binding groove reflects the folding of segments of the MHCII molecule into helices around the peptide with a concomitant folding of the peptide into a polyproline helix. The implications of cooperativity for peptide/MHCII structure and epitope selection are discussed.