Regulation of heterotypic claudin compatibility
Regulation of heterotypic claudin compatibility
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DOI：
10.1074/jbc.m703547200
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发表时间：
2007-10-12
影响因子：
4.8
通讯作者：
Koval, Michael
中科院分区：
文献类型：
--
作者：
Daugherty, Brandy L.;Ward, Christina;Koval, Michael
组织屏障功能直接由紧密连接跨膜蛋白（称为claudins）介导。形成紧密连接的细胞通常表达多种紧密连接蛋白亚型，这表明不同紧密连接蛋白亚型之间的异型（头对头）结合可能在调节细胞旁通透性中起作用。然而，鲜为人知的是控制异型claudin相容性的基序。我们发现，虽然claudin-3和claudin-4在同一细胞中表达时是异源相容的，但尽管具有在氨基酸水平上高度保守的细胞外环（EL）结构域，它们并不异源相互作用。与密蛋白-3异型相容的密蛋白-1和密蛋白-5不异型结合密蛋白-4。相比之下，含有紧密连接蛋白-3的第一EL结构域或第二EL结构域的紧密连接蛋白-4嵌合体能够异型结合紧密连接蛋白-1、紧密连接蛋白-3和紧密连接蛋白-5。此外，将Asn（44）转化为密蛋白-4中的相应氨基酸（Thr）的密蛋白-3的第一胞外环结构域中的单点突变产生能够异型结合密蛋白-4同时仍保留结合密蛋白-1和-5的能力的密蛋白。因此，异型密蛋白-密蛋白相互作用的控制对EL结构域的微小变化敏感。
Tissue barrier function is directly mediated by tight junction transmembrane proteins known as claudins. Cells that form tight junctions typically express multiple claudin isoforms which suggests that heterotypic (head-to-head) binding between different claudin isoforms may play a role in regulating paracellular permeability. However, little is known about motifs that control heterotypic claudin compatibility. We found that although claudin-3 and claudin-4 were heteromerically compatible when expressed in the same cell, they did not heterotypically interact despite having extracellular loop (EL) domains that are highly conserved at the amino acid level. Claudin-1 and -5, which were heterotypically compatible with claudin-3, did not heterotypically bind to claudin-4. In contrast, claudin-4 chimeras containing either the first EL domain or the second EL domain of claudin-3 were able to heterotypically bind to claudin-1, claudin-3, and claudin-5. Moreover, a single point mutation in the first extracellular loop domain of claudin-3 to convert Asn(44) to the corresponding amino acid in claudin-4 (Thr) produced a claudin capable of heterotypic binding to claudin-4 while still retaining the ability to bind to claudin-1 and -5. Thus, control of heterotypic claudin-claudin interactions is sensitive to small changes in the EL domains.