Biosynthesis, structure, and folding of the insulin precursor protein.
Biosynthesis, structure, and folding of the insulin precursor protein.
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胰岛素前体蛋白的生物合成、结构和折叠
DOI：
10.1111/dom.13378
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Arvan P
中科院分区：
文献类型：
--
作者：
Liu M;Weiss MA;Arunagiri A;Yong J;Rege N;Sun J;Haataja L;Kaufman RJ;Arvan P
胰腺β细胞中的胰岛素合成起始于前胰岛素原。餐前和餐后葡萄糖浓度的振荡，在前胰岛素原生物合成中产生主要的动态变化。伴随的胰岛素前体的上调翻译包括内质网（ER）易位装置的元件，其与前胰岛素原的信号肽的成功定向、易位和信号肽切割相关-所有这些都是启动适当胰岛素原折叠的途径所必需的。胰岛素原本身的一级结构上的进化压力保持了折叠的效率（“可折叠性”），值得注意的是，这些进化压力与保护胰岛素最终生物活性的压力不同。胰岛素原折叠性在ER中表现出来，其中局部环境被设计为有助于胰岛素原折叠的总体负荷并有利于其二硫键形成（同时限制错误折叠），所有这些都与ER应激反应途径密切相关，这些应激反应途径对胰腺β细胞具有复杂的（有益的，以及潜在的破坏性）作用。胰岛素原错误折叠可能是由于ER中胰岛素原生物合成负荷旺盛、胰岛素原编码序列突变或导致ER折叠环境改变的遗传倾向所致。胰岛素原错误折叠是一种与胰岛素产生缺陷和糖尿病密切相关的表型，如在各种情况下所见：携带胰岛素原错误折叠突变体的啮齿动物模型，具有突变INS基因诱导的青年糖尿病的人类患者，在关键ER驻留蛋白中携带突变的动物模型和人类患者，以及很可能在更常见的2型糖尿病中。
Insulin synthesis in pancreatic beta cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and post-prandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor include elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation, and signal peptide cleavage of preproinsulin — all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding (“foldability”), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favor its disulfide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic beta cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene induced Diabetes of Youth, animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.
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影响因子：
16.6
作者：
Back SH;Kaufman RJ
通讯作者：
Kaufman RJ
影响因子：
3.7
作者：
Cassel R;Ducreux S;Alam MR;Dingreville F;Berlé C;Burda-Jacob K;Chauvin MA;Chikh K;Païta L;Al-Mawla R;Crola Da Silva C;Rieusset J;Thivolet C;Van Coppenolle F;Madec AM
通讯作者：
Madec AM
影响因子：
8.1
作者：
Blutke A;Renner S;Flenkenthaler F;Backman M;Haesner S;Kemter E;Ländström E;Braun-Reichhart C;Albl B;Streckel E;Rathkolb B;Prehn C;Palladini A;Grzybek M;Krebs S;Bauersachs S;Bähr A;Brühschwein A;Deeg CA;De Monte E;Dmochewitz M;Eberle C;Emrich D;Fux R;Groth F;Gumbert S;Heitmann A;Hinrichs A;Keßler B;Kurome M;Leipig-Rudolph M;Matiasek K;Öztürk H;Otzdorff C;Reichenbach M;Reichenbach HD;Rieger A;Rieseberg B;Rosati M;Saucedo MN;Schleicher A;Schneider MR;Simmet K;Steinmetz J;Übel N;Zehetmaier P;Jung A;Adamski J;Coskun Ü;Hrabě de Angelis M;Simmet C;Ritzmann M;Meyer-Lindenberg A;Blum H;Arnold GJ;Fröhlich T;Wanke R;Wolf E
通讯作者：
Wolf E
影响因子：
29
作者：
Back SH;Scheuner D;Han J;Song B;Ribick M;Wang J;Gildersleeve RD;Pennathur S;Kaufman RJ
通讯作者：
Kaufman RJ
DOI：
10.1098/rstb.1988.0058
发表时间：
1988-07-06
影响因子：
6.3
作者：
BAKER, EN;BLUNDELL, TL;VIJAYAN, NM
通讯作者：
VIJAYAN, NM