Interdomain interface-mediated target recognition by the Scribble PDZ34 supramodule
Interdomain interface-mediated target recognition by the Scribble PDZ34 supramodule
复制标题
Scribble PDZ34 超模块的域间界面介导的目标识别
DOI：
10.1042/bj20141473
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发表时间：
2015
影响因子：
4.1
通讯作者：
Feng Wei
中科院分区：
文献类型：
--
作者：
Ren Jinqi;Feng Lei;Bai Yujie;Pei Haohong;Yuan Zengqiang;Feng Wei
串联排列的PDZ [PSD-95（突触后密度-95），Dlg（椎间盘大同源物）和ZO-1（封闭带-1）]结构域通常形成具有不同靶标结合特性的结构和功能超模块。在本研究中，我们发现细胞极性调节器Scribble的PDZ34串联中的两个PDZ结构域以“前后”模式紧密排列，形成紧凑的超模。虽然PDZ4含有扭曲的αB/βB口袋，但PDZ4与PDZ3的附着会产生一个意想不到的域间口袋，该口袋与PDZ3的典型αB/βB口袋相邻并集成，形成一个扩展的靶结合槽。pdz34 -靶肽复合物的结构进一步表明，该肽与这个扩展的靶结合槽结合，其上游残基直接锚定在域间口袋中。结构域间口袋的突变和PDZ34超模的破坏都会干扰其靶结合能力。因此，PDZ34超模之间的域间接口是其识别靶标所必需的，并决定了其结合靶标的特异性。这种域间接口介导的特异性识别可能代表了一种新的目标识别模式，并将扩大PDZ超模块与目标结合的多功能性。本研究发现的PDZ34串联的超模性和目标识别模式也有助于识别Scribble的新结合伙伴，从而可能指导进一步研究PDZ结构域介导的Scribble极性复合物的组装。
Tandem-arranged PDZ [PSD-95 (postsynaptic density-95), Dlg (discs large homologue) and ZO-1 (zonula occludens-1)] domains often form structural and functional supramodules with distinct target-binding properties. In the present study, we found that the two PDZ domains within the PDZ34 tandem of Scribble, a cell polarity regulator, tightly pack in a ‘front-to-back’ mode to form a compact supramodule. Although PDZ4 contains a distorted αB/βB pocket, the attachment of PDZ4 to PDZ3 generates an unexpected interdomain pocket that is adjacent to and integrates with the canonical αB/βB pocket of PDZ3 to form an expanded target-binding groove. The structure of the PDZ34–target peptide complex further demonstrated that the peptide binds to this expanded target-binding groove with its upstream residues anchoring into the interdomain pocket directly. Mutations of the interdomain pocket and disruptions of the PDZ34 supramodule both interfere with its target-binding capacity. Therefore, the interdomain interface between the PDZ34 supramodule is intrinsically required for its target recognition and determines its target-binding specificity. This interdomain interface-mediated specific recognition may represent a novel mode of target recognition and would broaden the target-binding versatility for PDZ supramodules. The supramodular nature and target recognition mode of the PDZ34 tandem found in the present study would also help to identify the new binding partners of Scribble and thus may direct further research on the PDZ domain-mediated assembly of Scribble polarity complexes.