Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden.
J Cell Sci. 2011 Sep 15;124(Pt 18):3074-83. doi: 10.1242/jcs.076943. Epub 2011 Aug 18.
The transmembrane mucins in the enterocyte are type 1 transmembrane proteins with long and rigid mucin domains, rich in proline, threonine and serine residues that carry numerous O-glycans. Three of these mucins, MUC3, MUC12 and MUC17 are unique in harboring C-terminal class I PDZ motifs, making them suitable ligands for PDZ proteins. A screening of 123 different human PDZ domains for binding to MUC3 identified a strong interaction with the PDZ protein GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein). This interaction was mediated by the C-terminal PDZ motif of MUC3, binding to the single GOPC PDZ domain. GOPC is also a binding partner for cystic fibrosis transmembrane conductance regulator (CFTR) that directs CFTR for degradation. Overexpression of GOPC downregulated the total levels of MUC3, an effect that was reversed by introducing CFTR. The results suggest that CFTR and MUC3 compete for binding to GOPC, which in turn can regulate levels of these two proteins. For the first time a direct coupling between mucins and the CFTR channel is demonstrated, a finding that will shed further light on the still poorly understood relationship between cystic fibrosis and the mucus phenotype of this disease.
肠上皮细胞中的跨膜粘蛋白是具有长而刚性粘蛋白结构域的 1 型跨膜蛋白，富含脯氨酸、苏氨酸和丝氨酸残基，这些残基携带许多 O-聚糖。这三种粘蛋白 MUC3、MUC12 和 MUC17 独特之处在于它们含有 C 末端的 I 类 PDZ 基序，使它们成为 PDZ 蛋白的合适配体。对 123 种不同的人 PDZ 结构域进行了与 MUC3 结合的筛选，结果发现与 PDZ 蛋白 GOPC（与高尔基体相关的 PDZ 和卷曲螺旋结构域蛋白）具有强烈的相互作用。这种相互作用是由 MUC3 的 C 末端 PDZ 基序介导的，与 GOPC 的单个 PDZ 结构域结合。GOPC 也是囊性纤维化跨膜电导调节因子 (CFTR) 的结合伙伴，它将 CFTR 导向降解。GOPC 的过表达下调了 MUC3 的总水平，而引入 CFTR 则逆转了这种作用。结果表明 CFTR 和 MUC3 竞争与 GOPC 结合，这反过来又可以调节这两种蛋白的水平。这是首次证明粘蛋白和 CFTR 通道之间存在直接偶联，这一发现将进一步阐明囊性纤维化和该疾病粘液表型之间仍然知之甚少的关系。
