Post-translational modifications of ICA512, a receptor tyrosine phosphatase-like protein of secretory
Post-translational modifications of ICA512, a receptor tyrosine phosphatase-like protein of secretory
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DOI：
10.1046/j.1460-9568.1999.00677.x
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发表时间：
1999-08-01
影响因子：
3.4
通讯作者：
Solimena, M
中科院分区：
文献类型：
--
作者：
Hermel, JM;Dirkx, R;Solimena, M
I型糖尿病自身抗原ICA512是一种受体酪氨酸磷酸酶样蛋白，丰富于神经元分泌颗粒膜和分泌多肽的内分泌细胞。虽然ICA512的功能尚不清楚，但它被认为将调节的神经肽和多肽激素的分泌与涉及酪氨酸磷酸化/去磷酸化的信号转导通路联系起来。为了进一步研究它的生化特性，我们在牛脑垂体和各种人ICA512构建的成纤维细胞中进行了研究，牛脑垂体是天然ICA512的丰富来源。基于这些研究，我们已经确定ICA512的信号肽包含1-34个残基，ICA512的胞外结构域经历了多种翻译后修饰，包括N-糖基化。新合成的ICA512首先作为110 kDa的前蛋白出现，然后通过翻译后修饰转换成130 kDa的物种。前-ICA512在呋喃类转换酶的共识下被切割产生一个60-66 kDa的ICA512跨膜片段(氨基酸449-979)。ICA512的这种处理并不局限于神经内分泌细胞，因为它也可以发生在转基因的成纤维细胞中。最后，由这种裂解产生的ICA512的N末端片段(氨基酸35-448)或其部分存在于垂体后叶的神经分泌体中，这增加了它们可能在分泌颗粒分泌时被分泌的可能性。
The autoantigen of type I diabetes ICA512 is a receptor tyrosine phosphatase-like protein enriched in the secretory granule membranes of neurons and peptide secreting endocrine cells. While the function of ICA512 remains unknown, it is thought to link regulated neuropeptide and peptide hormone secretion with signal transduction pathways involving tyrosine phosphorylation/dephosphorylation. To characterize further its biochemical properties, we conducted studies in the bovine pituitary, an abundant source of native ICA512, as well as in fibroblasts transfected with various human ICA512 cDNA constructs. Based on these studies we have established that the signal peptide of ICA512 encompasses residues 1-34 and that the ectodomain of ICA512 undergoes multiple post-translation modifications, including N-glycosylation. Newly synthesized ICA512 appears first as a pro-protein of 110 kDa that is then converted by post-translational modifications into a 130-kDa species. Cleavage of pro-ICA512 at a consensus for furin-like convertases generates a 60-66-kDa ICA512 transmembrane fragment (amino acids 449-979). Such processing ICA512 is not restricted to neuroendocrine cells, as it can also occur in transfected fibroblasts. Finally, the predicted N-terminal fragment of ICA512 resulting from this cleavage (amino acids 35-448) or parts thereof are present in the neurosecretosomes of posterior pituitary, raising the possibility that they may be secreted upon exocytosis of secretory granules.