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首页> 外文期刊>Journal of Molecular Biology >Structures of Human CCL18, CCL3, and CCLA Reveal Molecular Determinants for Quaternary Structures and Sensitivity to Insulin-Degrading Enzyme
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Structures of Human CCL18, CCL3, and CCLA Reveal Molecular Determinants for Quaternary Structures and Sensitivity to Insulin-Degrading Enzyme

机译：人类CCL18，CCL3和CCLA的结构揭示了四级结构的分子决定因素和对胰岛素降解酶的敏感性。

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CC chemokine ligands (CCLs) are 8- to 14-kDa signaling proteins involved in diverse immune functions. While CCLs share similar tertiary structures, oligomerization produces highly diverse quaternary structures that protect chemokines from proteolytic degradation and modulate their functions. CCL18 is closely related to CCL3 and CCL4 with respect to both protein sequence and genomic location, yet CCL18 has distinct biochemical and biophysical properties. Here, we report a crystal structure of human CCL18 and its oligomerization states in solution based on crystallographic and small-angle X-ray scattering analyses. Our data show that CCL18 adopts an alpha-helical conformation at its N-terminus that weakens its dimerization, explaining CCL18's preference for the monomeric state. Multiple contacts between monomers allow CCL18 to reversibly form a unique open-ended oligomer different from those of CCL3, CCL4, and CCL5. Furthermore, these differences hinge on proline 8, which is conserved in CCL3 and CCL4 but is replaced by lysine in human CCL18. Our structural analyses suggest that a mutation of proline 8 to alanine stabilizes a type 1 beta-turn at the N-terminus of CCL4 to prevent dimerization but prevents dimers from making key contacts with each other in CCL3. Thus, the P8A mutation induces depolymerization of CCL3 and CCL4 by distinct mechanisms. Finally, we used structural, biochemical, and functional analyses to unravel why insulin-degrading enzyme degrades CCL3 and CCL4 but not CCL18. Our results elucidate the molecular basis for the oligomerization of three closely related CC chemokines and suggest how oligomerization shapes CCL chemokine function. (C) 2015 Elsevier Ltd. All rights reserved.
机译：CC趋化因子配体（CCL）是参与多种免疫功能的8至14 kDa信号蛋白。虽然CCL具有相似的三级结构，但低聚会产生高度多样化的四级结构，从而保护趋化因子免受蛋白水解降解并调节其功能。就蛋白质序列和基因组位置而言，CCL18与CCL3和CCL4密切相关，但CCL18具有独特的生化和生物物理特性。在这里，我们根据晶体学和小角度X射线散射分析报告了人类CCL18的晶体结构及其在溶液中的低聚状态。我们的数据表明，CCL18在其N端采用α螺旋构象，从而削弱了其二聚化作用，这说明了CCL18对于单体态的偏爱。单体之间的多次接触使CCL18可逆地形成不同于CCL3，CCL4和CCL5的独特的开放式低聚物。此外，这些差异取决于脯氨酸8，脯氨酸在CCL3和CCL4中是保守的，但在人CCL18中被赖氨酸取代。我们的结构分析表明，脯氨酸8突变为丙氨酸可稳定CCL4 N端的1型β-转角，从而防止二聚化，但防止二聚体在CCL3中彼此形成关键接触。因此，P8A突变通过不同的机制诱导CCL3和CCL4的解聚。最后，我们使用结构，生化和功能分析来阐明为什么胰岛素降解酶降解CCL3和CCL4而不降解CCL18的原因。我们的研究结果阐明了三种密切相关的CC趋化因子低聚的分子基础，并提出了低聚如何影响CCL趋化因子功能的。 （C）2015 Elsevier Ltd.保留所有权利。

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