胰岛素加工
中文名称
通路描述
从内质网（ER）腔中新生合成的前胰岛素生成包含胰岛素的分泌颗粒涉及前胰岛素分子内二硫键的形成、前胰岛素锌钙复合物的形成、前胰岛素的前胰岛素切割以产生胰岛素和 C 肽，以及颗粒穿越细胞质到达质膜（Dodson & Steiner 1998）。转录的人类胰岛素基因 INS 被注释为“β细胞中基因表达调节”途径的一部分（参见反应 R-HSA-211289）。前胰岛素 mRNA 由粗面内质网（ER）上的核糖体翻译，前胰岛素通过其信号肽进入分泌途径，该信号肽在共翻译过程中被切割以产生前胰岛素。在此标注的进程中，在内质网中，三个分子内二硫键由 P4HD（PDI1A）和 ERO1B 蛋白形成。正确折叠的二硫键结合的前胰岛素然后通过囊泡从 ER 移动到高尔基复合体，在那里它与锌和钙形成复合物。前胰岛素锌钙复合物从转高尔基体形成囊泡，形成细胞质中的未成熟分泌颗粒（分泌颗粒）。在未成熟颗粒内，内肽酶 PCKS1 和 PCKS2（前体蛋白转化酶 1 和 2）在两个位点切割前胰岛素，CPE（羧肽酶 E）去除额外的氨基酸残基，产生成熟胰岛素和 C 肽的胱氨酸结合 A 和 B 链，这些将随胰岛素一起分泌。胰岛素锌钙复合物在颗粒内形成不溶性晶体。随后，包含胰岛素的分泌颗粒穿越细胞质到达质膜的内表面。转移最初是通过颗粒与 Kinesin 1 的结合实现的，该颗粒沿微管移动，然后是通过与肌动蛋白微丝网络（细胞皮层微丝系统）中的肌动蛋白 Va 的结合实现的。胰腺β细胞含有约 10,000 个胰岛素颗粒，其中约 1,000 个锚定在质膜上，50 个在葡萄糖或其他分泌诱导物刺激后立即可释放。锚定是由于颗粒膜上的 Exocyst 蛋白 EXOC3 与质膜上的 EXOC4 之间的相互作用引起的。胞吐是通过质膜上的 Syntaxin 1A 和 Syntaxin 4 与颗粒膜上的 Synaptobrevin 2/VAMP2 之间的相互作用实现的。胞吐是一种钙依赖性过程，这是由于钙结合膜蛋白 Synaptotagmin V/IX 与 SNARE 类型蛋白之间的相互作用引起的。
英文描述
Insulin processing Generation of insulin containing secretory granules from newly synthesized proinsulin in the lumen of the endoplasmic reticulum (ER) involves formation of proinsulin intramolecular disulfide bonds, formation of proinsulin zinc calcium complexes, proteolytic cleavage of proinsulin to yield insulin and C peptide, and translocation of the granules across the cytosol to the plasma membrane (Dodson & Steiner 1998).
Transcription of the human insulin gene INS is annotated as part of the pathway âRegulation of gene expression in beta cellsâ (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.
In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.
Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.
The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.
Transcription of the human insulin gene INS is annotated as part of the pathway âRegulation of gene expression in beta cellsâ (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.
In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.
Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.
The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.
所含基因
25 个基因