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Integrative Model to Coordinate the Oligomerization and Aggregation Mechanisms of CCL5

机译：综合模型协调CCL5的低聚和聚集机制

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摘要

CC-type chemokine ligand 5 (CCL5) is involved in the pathogenesis of many inflammatory conditions. Under physiological conditions, CCL5 oligomerization and aggregation are considered to be responsible for its inflammatory properties. The structural basis of CCL5 oligomerization remains controversial because the current oligomer models contain no consensus interactions. In this study, NMR and biophysical analyses proposed evidence that the CC-type CCL5 dimer acts as the basic unit to constitute the oligomer and that CCL5 oligomerizes alternatively through E66-K25 and E66-R44/K45 interactions. In addition, a newly determined trimer structure, constituted by CCL5 and the E66S mutant, reported an interfacial interaction through the N-terminal (12)FAY(14) sequence. The interaction contributes to CCL5 aggregation and precipitation but not to oligomerization. In accordance with the observations, an integrative model explains the CCL5 oligomerization and aggregation mechanism in which CCL5 assembly consists of two types of dimer-dimer interactions and one aggregation mechanism. For full-length CCL5, the molecular accumulation triggers oligomerization through the E66-K25 and E66-R44/K45 interactions, and the (12)FAY(14) interaction acts as a secondary effect to derive aggregation and precipitation. In contrast, the E66-R44/K45 interaction might dominate in CCL5 N-terminal truncations, and the interaction would lead to the filament-like formation in solution. (C) 2020 Elsevier Ltd. All rights reserved.
机译：CC型趋化因子配体5（CCL5）参与许多炎症病症的发病机制。在生理条件下，CCL5寡聚化和聚集被认为是其炎症性质的原因。 CCL5低聚的结构基础仍然存在争议，因为目前的低聚物模型含有不含有共识相互作用。在本研究中，NMR和生物物理学分析提出了CC-型CCl5二聚体作为基本单元构成低聚物的作用，并且CCL5通过E66-K25和E66-R44 / K45相互作用来脱氧。另外，由CCL5和E66S突变体构成的新确定的三聚体结构报道了通过N-末端（12）Fay（14）序列的界面相互作用。相互作用有助于CCl5聚集和沉淀，但不含低聚。根据观察结果，一体化模型解释了CCl5寡聚化和聚集机制，其中CCL5组件由两种类型的二聚体相互作用和一种聚集机制组成。对于全长CCl5，分子累积通过E66-K25和E66-R44 / K45相互作用触发寡聚，（12）烃（14）相互作用作为衍生聚集和沉淀的二次效果。相反，E66-R44 / K45相互作用可能在CCL5 N-末端截短中占主导地位，并且相互作用将导致溶液中的丝状形成。 （c）2020 elestvier有限公司保留所有权利。

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