Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Germany.
Ann N Y Acad Sci. 2012 Jun;1257:38-44. doi: 10.1111/j.1749-6632.2012.06536.x.
Tight junctions (TJs) form paracellular barriers defining the permeability characteristics of epithelial and endothelial cell layers in our body. Tetraspanin integral membrane proteins, including occludin, tricellulin, MarvelD3, and a set of claudins, form a network of anastomosing strands bringing the membranes of neighboring cells into close contact. Occludin is assumed to play an important role in the regulation of TJ formation, structure, and function, and is tightly regulated by phosphorylation. We here summarize the role of occludin phosphorylation on assembly/disassembly and function of TJs and specifically focus on a cluster of 11 amino acids in the C-terminal cytoplasmic domain of occludin (Tyr398-Ser408), including highly conserved phosphorylation sites for c-Src, PKCs, and CK2. Phosphorylation by these kinases affects occludin localization, dynamics, and interaction with other TJ proteins. Interestingly, this phosphorylation hotspot is localized in an unstructured region close to the ZO-1 binding site, and a cysteine residue which is involved in intermolecular disulfide-bond formation thus contributing to occludin dimerization. We discuss potential consequences and open questions in respect to the functional role of this phosphorylation hotspot.
紧密连接（TJs）形成细胞旁屏障，定义了我们体内上皮细胞和内皮细胞层的渗透性特征。四跨膜蛋白整合膜蛋白，包括occludin、tricellulin、MarvelD3 和一组 Claudin，形成一个吻合的网络，使相邻细胞的膜紧密接触。occludin 被认为在 TJ 的形成、结构和功能的调节中起着重要作用，并受到磷酸化的严格调节。我们在这里总结了 occludin 磷酸化在 TJ 组装/拆卸和功能中的作用，并特别关注 occludin 细胞质 C 末端（Tyr398-Ser408）的 11 个氨基酸簇，包括 c-Src、PKCs 和 CK2 的高度保守磷酸化位点。这些激酶的磷酸化影响 occludin 的定位、动力学和与其他 TJ 蛋白的相互作用。有趣的是，这个磷酸化热点位于靠近 ZO-1 结合位点的无规卷曲区域附近，以及一个半胱氨酸残基，它参与分子间二硫键的形成，从而有助于 occludin 二聚化。我们讨论了这个磷酸化热点在功能作用方面的潜在后果和未解决的问题。
