Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity
Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity
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DOI：
10.1016/s0167-4889(00)00109-9
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发表时间：
2000-12-11
影响因子：
5.1
通讯作者：
Frost, SC
中科院分区：
文献类型：
--
作者：
Hwang, JB;Hernandez, J;Frost, SC
葡萄糖剥夺导致3 T3-L1脂肪细胞中胰岛素前体受体的异常糖基化（“替代”）和低效加工形式的合成。为了进一步探索胰岛素受体的异常（而不是缺失）N-连接糖基化的影响，我们研究了加工与功能的关系。我们的研究表明，前受体的替代形式不寡聚化，也没有获得进行胰岛素敏感性自磷酸化的能力。这沿着与葡萄糖调节应激蛋白GRP 78/BiP的相互作用意味着不适当的折叠/二聚化和保留在ER中。葡萄糖再供给导致前受体的替代形式的翻译后修饰为新的“中间”形式，其独立于新的蛋白质合成。低至100 μ M的葡萄糖（或甘露糖）可以诱导这种修饰。在体外消化的替代和中间前受体与SPC 1/弗林蛋白酶显示，α-和β-亚基结构域的糖基化，虽然异常。这意味着如果受体能够在适当的区室中与酶相互作用（即，trans-Golgi网络）。然而，基于抑制剂研究，前受体的替代形式和中间形式似乎主要针对蛋白酶体进行降解。(C)2000 Elsevier Science B. V.保留所有权利。
Glucose deprivation leads to the synthesis of an aberrantly glycosylated ('alternative') and inefficiently processed form of the insulin proreceptor in 3T3-L1 adipocytes. To further explore the effect of aberrant (rather than absent) N-linked glycosylation of the insulin receptor, we examined the relationship of processing to function. Our studies show that the alternative form of the proreceptor does not oligomerize nor does it acquire the ability to undergo insulin-sensitive autophosphorylation. This along with an interaction with the glucose-regulated stress protein GRP78/BiP implies inappropriate folding/dimerization and retention in the ER. Glucose refeeding causes the post-translational modification of the alternative form of the proreceptor to a novel 'intermediate' form which is independent of new protein synthesis. As little as 100 muM glucose (or mannose) can induce this modification. In vitro digestion of the alternative and intermediate proreceptors with SPC1/furin shows that both the alpha- and beta -subunit domains are glycosylated, albeit aberrantly. This implies that the aberrantly glycosylated proreceptor could serve as a substrate for SPC1 in a physiological setting if the receptor was able to interact with the enzyme in the appropriate compartment (i.e., the trans-Golgi network). Based on inhibitor studies, however, both the alternative and intermediate forms of the proreceptor appear to be primarily targeted to the proteasome for degradation. (C) 2000 Elsevier Science B.V. All rights reserved.