Insulin processing (Homo sapiens)
From WikiPathways
Description
The generation of insulin-containing secretory granules from proinsulin in the lumen of the endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.
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 cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.
In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha
The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin 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 the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also 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 10000 insulin granules of which about 1000 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. View original pathway at:Reactome.
Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.
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 cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.
In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha
The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin 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 the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also 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 10000 insulin granules of which about 1000 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. View original pathway at:Reactome.
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- Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S.; ''Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.''; PubMed Europe PMC Scholia
- Liu M, Li Y, Cavener D, Arvan P.; ''Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum.''; PubMed Europe PMC Scholia
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History
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External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| 2xHC-INS(25-54) | Protein | P01308 (Uniprot-TrEMBL)  | |
| 4xHC-INS(90-110) | Protein | P01308 (Uniprot-TrEMBL) | |
| 6xHC-INS(25-110) | Protein | P01308 (Uniprot-TrEMBL) | |
| 6xHC-INS(25-110) | Protein | P01308 (Uniprot-TrEMBL) | |
| 6xInsulin:2xZn2+:Ca2+ (docked granule) | Complex | R-HSA-386977 (Reactome) | |
| 6xInsulin:2xZn2+ | Complex | R-HSA-264931 (Reactome) | |
| 6xProinsulin:2xZn2+:1xCa2+ | Complex | R-HSA-264908 (Reactome) | |
| 6xProinsulin:2xZn2+:1xCa2+ | Complex | R-HSA-265073 (Reactome) | |
| Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
| Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
| Carboxypeptidase | Complex | R-HSA-3229254 (Reactome) | This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis. |
| Core SNARE Complex | Complex | R-HSA-387383 (Reactome) | |
| EROIL-like Proteins | Complex | R-HSA-4084703 (Reactome) | This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis. |
| EXOC1 | Protein | Q9NV70 (Uniprot-TrEMBL) | |
| EXOC1 | Protein | Q9NV70 (Uniprot-TrEMBL) | |
| EXOC2 | Protein | Q96KP1 (Uniprot-TrEMBL) | |
| EXOC2 | Protein | Q96KP1 (Uniprot-TrEMBL) | |
| EXOC3 | Protein | O60645 (Uniprot-TrEMBL) | |
| EXOC3 | Protein | O60645 (Uniprot-TrEMBL) | |
| EXOC4 | Protein | Q96A65 (Uniprot-TrEMBL) | |
| EXOC4 | Protein | Q96A65 (Uniprot-TrEMBL) | |
| EXOC5 | Protein | O00471 (Uniprot-TrEMBL) | |
| EXOC5 | Protein | O00471 (Uniprot-TrEMBL) | |
| EXOC6 | Protein | Q8TAG9 (Uniprot-TrEMBL) | |
| EXOC6 | Protein | Q8TAG9 (Uniprot-TrEMBL) | |
| EXOC7 | Protein | Q9UPT5 (Uniprot-TrEMBL) | |
| EXOC7 | Protein | Q9UPT5 (Uniprot-TrEMBL) | |
| EXOC8 | Protein | Q8IYI6 (Uniprot-TrEMBL) | |
| EXOC8 | Protein | Q8IYI6 (Uniprot-TrEMBL) | |
| Exocyst Complex | Complex | R-HSA-264974 (Reactome) | |
| INS(25-110) | Protein | P01308 (Uniprot-TrEMBL) | |
| INS(57-87) | Protein | P01308 (Uniprot-TrEMBL) | |
| KIF5B-like proteins | Complex | R-HSA-3878118 (Reactome) | This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis. |
| MYO5A | Protein | Q9Y4I1 (Uniprot-TrEMBL) | |
| PC1:calcium cofactor | Complex | R-HSA-378974 (Reactome) | |
| PCSK1 | Protein | P29120 (Uniprot-TrEMBL) | |
| PCSK2 | Protein | P16519 (Uniprot-TrEMBL) | |
| RAB27A | Protein | P51159 (Uniprot-TrEMBL) | |
| SLC30A5 | Protein | Q8TAD4 (Uniprot-TrEMBL) | |
| SLC30A6 | Protein | Q6NXT4 (Uniprot-TrEMBL) | |
| SLC30A7 | Protein | Q8NEW0 (Uniprot-TrEMBL) | |
| SLC30A8 | Protein | Q8IWU4 (Uniprot-TrEMBL) | |
| STX1A | Protein | Q16623 (Uniprot-TrEMBL) | |
| VAMP2 | Protein | P63027 (Uniprot-TrEMBL) | |
| Zn2+ | Metabolite | CHEBI:29105 (ChEBI) | |
| Zn2+ | Metabolite | CHEBI:29105 (ChEBI) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 6xHC-INS(25-110) | Arrow | R-HSA-264997 (Reactome) | ||
| 6xHC-INS(25-110) | Arrow | R-HSA-265010 (Reactome) | ||
| 6xHC-INS(25-110) | R-HSA-264976 (Reactome) | |||
| 6xHC-INS(25-110) | R-HSA-265010 (Reactome) | |||
| 6xInsulin:2xZn2+:Ca2+ (docked granule) | Arrow | R-HSA-265178 (Reactome) | ||
| 6xInsulin:2xZn2+ | Arrow | R-HSA-265160 (Reactome) | ||
| 6xInsulin:2xZn2+ | Arrow | R-HSA-265179 (Reactome) | ||
| 6xInsulin:2xZn2+ | R-HSA-265160 (Reactome) | |||
| 6xInsulin:2xZn2+ | R-HSA-265178 (Reactome) | |||
| 6xProinsulin:2xZn2+:1xCa2+ | Arrow | R-HSA-264976 (Reactome) | ||
| 6xProinsulin:2xZn2+:1xCa2+ | Arrow | R-HSA-265153 (Reactome) | ||
| 6xProinsulin:2xZn2+:1xCa2+ | R-HSA-265153 (Reactome) | |||
| 6xProinsulin:2xZn2+:1xCa2+ | R-HSA-265179 (Reactome) | |||
| Ca2+ | R-HSA-264976 (Reactome) | |||
| Carboxypeptidase | mim-catalysis | R-HSA-265179 (Reactome) | ||
| Core SNARE Complex | mim-catalysis | R-HSA-265178 (Reactome) | ||
| EROIL-like Proteins | mim-catalysis | R-HSA-264997 (Reactome) | ||
| EXOC1 | R-HSA-265177 (Reactome) | |||
| EXOC2 | R-HSA-265177 (Reactome) | |||
| EXOC3 | R-HSA-265177 (Reactome) | |||
| EXOC4 | R-HSA-265177 (Reactome) | |||
| EXOC5 | R-HSA-265177 (Reactome) | |||
| EXOC6 | R-HSA-265177 (Reactome) | |||
| EXOC7 | R-HSA-265177 (Reactome) | |||
| EXOC8 | R-HSA-265177 (Reactome) | |||
| Exocyst Complex | Arrow | R-HSA-265177 (Reactome) | ||
| INS(25-110) | R-HSA-264997 (Reactome) | |||
| INS(57-87) | Arrow | R-HSA-265179 (Reactome) | ||
| KIF5B-like proteins | mim-catalysis | R-HSA-265160 (Reactome) | ||
| MYO5A | mim-catalysis | R-HSA-265178 (Reactome) | ||
| PC1:calcium cofactor | mim-catalysis | R-HSA-265179 (Reactome) | ||
| PCSK2 | mim-catalysis | R-HSA-265179 (Reactome) | ||
| R-HSA-264976 (Reactome) | In the presence of high concentrations of zinc and calcium, proinsulin spontaneously forms soluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. Zinc Transporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells (and also in many other cell types). They play a role in maintaining the high zinc concentration in the Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Other transporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this is presently unknown. | |||
| R-HSA-264997 (Reactome) | Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteine residues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directly catalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizing environment for the reactions to occur . Though Ero1-like alpha can act via specific isomerases such as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulin requires a specific isomerase. Interestingly, even in beta cells of wild type animals, trace amounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystine bonds may involve a period of bond shuffling. | |||
| R-HSA-265010 (Reactome) | Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud from the endoplasmic reticulum. | |||
| R-HSA-265153 (Reactome) | Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from the trans-golgi network. | |||
| R-HSA-265160 (Reactome) | Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin) from the trans-golgi to the cellular cortex. Motor activity is provided by Dynamin-1 but the complex that connects the secretory granule to the Kinesin-1 is not yet fully known. The process is stimulated by intracellular calcium ions (Ca2+). | |||
| R-HSA-265177 (Reactome) | A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). As inferred from rat MIN6 cells, docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane (Matern et al. 2001). | |||
| R-HSA-265178 (Reactome) | Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex of uncertain composition. Myosin Va moves along the cortical actin network (actin at the periphery of the cytoplasm), carrying the granules to the inner surface of the plasma membrane. A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). Docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane. Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. | |||
| R-HSA-265179 (Reactome) | Proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases Convertase 1/3 and Convertase 2. The exopeptidase Carboxypeptidase E then removes 2 amino acids from the carboxyl termini. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules. | |||
| R-HSA-437085 (Reactome) | The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressed but is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5 mediates the transport of zinc into secretory granules that contain insulin. | |||
| R-HSA-437129 (Reactome) | The human gene SLC30A7 encodes the zinc transporter ZnT7. It is thought to be present in the small intestine and lung in humans (Kirschke CP and Huang L, 2003). Functional properties assigned to ZnT7 are based on studies conducted with mouse experiments. | |||
| R-HSA-437136 (Reactome) | The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed in pancreatic beta cells (Chimienti et al. 2005). Zinc is required for zinc-insulin crystallization within secretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secreted locally in the extracellular matrix together with insulin. It has been suggested that this co-secreted zinc plays a role in islet cell paracrine and/or autocrine communication (Chimienti F et al, 2006). Loss of function mutations in SLC30A8 are strongly protective against type 2 diabetes, suggesting SLC20A8 inhibition as a therapeutic target in T2D prevention. (Flannick et al. 2014). | |||
| R-HSA-437139 (Reactome) | Two human genes mediate the transport of zinc into the TGN and they are both localized to the TGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies, ZnT6 is only found in the brain and lung in human (Huang L et al, 2002). | |||
| RAB27A | mim-catalysis | R-HSA-265178 (Reactome) | ||
| SLC30A5 | mim-catalysis | R-HSA-437085 (Reactome) | ||
| SLC30A6 | mim-catalysis | R-HSA-437139 (Reactome) | ||
| SLC30A7 | mim-catalysis | R-HSA-437129 (Reactome) | ||
| SLC30A8 | mim-catalysis | R-HSA-437136 (Reactome) | ||
| Zn2+ | Arrow | R-HSA-437085 (Reactome) | ||
| Zn2+ | Arrow | R-HSA-437129 (Reactome) | ||
| Zn2+ | Arrow | R-HSA-437136 (Reactome) | ||
| Zn2+ | Arrow | R-HSA-437139 (Reactome) | ||
| Zn2+ | R-HSA-264976 (Reactome) | |||
| Zn2+ | R-HSA-437085 (Reactome) | |||
| Zn2+ | R-HSA-437129 (Reactome) | |||
| Zn2+ | R-HSA-437136 (Reactome) | |||
| Zn2+ | R-HSA-437139 (Reactome) |
