The dyslexia-associated KIAA0319 protein undergoes proteolytic processing with {gamma}-secretase-independent intramembrane cleavage.
The dyslexia-associated KIAA0319 protein undergoes proteolytic processing with {gamma}-secretase-independent intramembrane cleavage.
复制标题
DOI：
10.1074/jbc.m110.145961
复制
发表时间：
2010-12-17
期刊：
影响因子：
--
通讯作者：
Monaco AP
中科院分区：
文献类型：
--
作者：
Velayos-Baeza A;Levecque C;Kobayashi K;Holloway ZG;Monaco AP
多项研究表明 KIAA0319 基因与阅读障碍有关。它编码具有大的、高度糖基化的胞外结构域的质膜蛋白。这种蛋白质被认为在粘附和附着中发挥作用，并被认为在发育中的大脑的神经元迁移过程中发挥重要作用。我们之前提出，这种蛋白质的内吞作用可能构成调节其功能的重要机制。在这里，我们展示了 KIAA0319 经历了胞外域脱落和膜内裂解。至少发生五种不同的切割事件，四种在胞外域中，一种在跨膜域中。胞外域脱落处理会裂解胞外域，产生几个小片段，包括具有富含 Cys 的 MANEC 域的 N 末端区域。这些片段可能被释放到细胞外介质并触发细胞反应。膜内裂解将细胞内结构域从其膜附着处释放。我们的结果表明，这种裂解事件不是由 γ-分泌酶执行的，γ-分泌酶是参与许多其他 I 型蛋白的类似加工的酶复合物。 KIAA0319 的可溶性胞质结构域能够易位至细胞核，在过表达后积聚在核仁中。该片段的作用未知，但可能参与基因表达的调节。 DNA相互作用基序的缺失表明这种功能很可能是通过与其他蛋白质的相互作用来介导的，而不是通过直接的DNA结合来介导。这些结果表明 KIAA0319 不仅在神经元迁移中具有直接作用，而且还可能具有额外的信号传导功能。
The KIAA0319 gene has been associated with reading disability in several studies. It encodes a plasma membrane protein with a large, highly glycosylated, extracellular domain. This protein is proposed to function in adhesion and attachment and thought to play an important role during neuronal migration in the developing brain. We have previously proposed that endocytosis of this protein could constitute an important mechanism to regulate its function. Here we show that KIAA0319 undergoes ectodomain shedding and intramembrane cleavage. At least five different cleavage events occur, four in the extracellular domain and one within the transmembrane domain. The ectodomain shedding processing cleaves the extracellular domain, generating several small fragments, including the N-terminal region with the Cys-rich MANEC domain. It is possible that these fragments are released to the extracellular medium and trigger cellular responses. The intramembrane cleavage releases the intracellular domain from its membrane attachment. Our results suggest that this cleavage event is not carried out by γ-secretase, the enzyme complex involved in similar processing in many other type I proteins. The soluble cytoplasmic domain of KIAA0319 is able to translocate to the nucleus, accumulating in nucleoli after overexpression. This fragment has an unknown role, although it could be involved in regulation of gene expression. The absence of DNA-interacting motifs indicates that such a function would most probably be mediated through interaction with other proteins, not by direct DNA binding. These results suggest that KIAA0319 not only has a direct role in neuronal migration but may also have additional signaling functions.