Proinsulin

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insulin
Insulin path.svg
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
Identifiers
SymbolINS
NCBI gene 3630
HGNC 6081
OMIM 176730
RefSeq NM_000207
UniProt P01308
Other data
Locus Chr. 11 p15.5
Search for
Structures Swiss-model
Domains InterPro

Proinsulin is the prohormone precursor to insulin made in the beta cells of the Pancreatic Islets, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. [1] [2] The pancreatic islets only secrete between 1% and 3% of proinsulin intact. [3] However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. [3] There are higher concentrations of proinsulin after meals and lower levels when a person is fasting. [3] Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin. [3]

Contents

Proinsulin is the final single chain protein structure secreted by cells before cleavage into mature insulin. [4] Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967. [5]

Structure

Proinsulin is made up of 86 residues in humans (81 in cows), [6] and formed by three distinct chains. [7] The A chain, B chain, and the area connecting the two named the C peptide. [7] The correct structure of proinsulin is crucial for the correct folding of mature insulin, as the placement of the C peptide sets the molecule up to create correctly positioned disulfide bonds in and between the A and B chains. [7] [8] There are three disulfide bonds that are necessary for mature insulin to be the correct structure. Two of these disulfide bonds are between the A and B chains, and one is an intra-A chain bond. [7] The disulfide bonds occur between the seventh residues of the A and B chain, the 20th residue of the A chain and the 19th residue of the B chain, and the 6th and 11th residues of the A chain. [9]

The C peptide is between the A and B chains of proinsulin. [7] The connection between the A chain and C peptide is much more stable than the junction between the C peptide and B chain, with alpha helical features being exhibited near the C peptide-A chain connection. [10] The C peptide-A chain junction occurs between residues 64 and 65 of proinsulin. These are lysine and arginine molecules, respectively. [10] The C peptide-B chain connection is between two arginine residues at positions 31 and 32 of proinsulin. [10]

There is conservation of much of the structure of proinsulin among mammalian species, with much of the residue changes seen from one species to another present in the C peptide. [8] [11] That said, the residues of the C peptide that are conserved across species interact with similarly conserved residues on the A and B chains. [8] Thus, it is hypothesized that these conserved residues are important for the functionality of mature insulin. [8]

Proinsulin 3.png
Proinsulin annotated.png
3D Model of proinsulin - A chain is in blue, b chain in red, c peptide in orange. The dibasic cleavage for c peptide and a chain is in green KR (lysine and arginine), the one for c peptide and b chain is in cyan RR (arginine).

Synthesis and Post-translational Modification

Proinsulin is synthesized on membrane associated ribosomes found on the rough endoplasmic reticulum, where it is folded and its disulfide bonds are oxidized. It is then transported to the Golgi apparatus where it is packaged into secretory vesicles, and where it is processed by a series of proteases to form mature insulin. Mature insulin has 35 fewer amino acids; 4 are removed altogether, and the remaining 31 form the C-peptide. The C-peptide is abstracted from the center of the proinsulin sequence; the two other ends (the B chain and A chain) remain connected by disulfide bonds.[ citation needed ]

The post translational modification of proinsulin to mature insulin only occurs in the beta cells of the pancreatic islets. [12] When proinsulin is transported through the Golgi apparatus the C-peptide is cleaved. [9] This cleavage occurs with the aid of two endoproteases. [13] Type I endoproteases, PC1 and PC3, disrupt the C peptide-B chain connection. [13] PC2, a type II endoprotease, cleaves the C peptide-A chain bond. [13] The resulting molecule, now mature insulin, is stored as a hexamer in secretory vesicles and is stabilized with ions until it is secreted. [9]

Proinsulin evolution.png

Immunogenicity

When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed. [14] [15] When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species. Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue. [16] With respect to their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may be of positive advantage to all diabetics without endogenous insulin secretion (e.g. people with type 1 diabetes) because insulin binding antibodies effectively increase the insulin's clearance rate and distribution space and help to prolong its pharmacological and biological half lives. [17] [ clarification needed ]

Medical Relevance

Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin or proinsulin:insulin ratio [18] in relation to these diseases has become increasingly clear.

Diabetes Mellitus

Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes. [19] Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding. [9] If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein. [9] This stress, after a while, would lead to a decrease in the number of β-cells producing mature insulin, and would then lead to diabetes mellitus. [9]

Neonatal Diabetes Mellitus

Postnatal proinsulin is crucial for metabolic regulation. However, proinsulin in neonates is important for normal development of the nerves of the eye, development of the heart, and general survival of embryonic cells. [20] Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus. [20] Thus far in the study of neonatal diabetes mellitus, only amino acid change mutations found in the B domain lead to the disease. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats, and protein by promoting the absorption of glucose from the blood into cells of the liver, fat, and skeletal muscles. In these tissues the absorbed glucose is converted into either glycogen, via glycogenesis, or fats (triglycerides), via lipogenesis; in the liver, glucose is converted into both. Glucose production and secretion by the liver are strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is thus an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules in the cells. Low insulin in the blood has the opposite effect, promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Protein</span> Biomolecule consisting of chains of amino acid residues

Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity.

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Post-translational modification</span> Chemical changes in proteins following their translation from mRNA

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">C-peptide</span> Chemical compound

The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can be used to distinguish between different conditions with similar clinical features.

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

<span class="mw-page-title-main">Insulin receptor</span> Cell receptor found in humans

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic gonadotropins, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant women and mares, respectively. The gonadotropins act on the gonads, controlling gamete and sex hormone production.

<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Proprotein convertase 1</span>

Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an enzyme that in humans is encoded by the PCSK1 gene. PCSK1 and PCSK2 differentially cleave proopiomelanocortin and they act together to process proinsulin and proglucagon in pancreatic islets.

<span class="mw-page-title-main">Vitronectin</span> Protein

Vitronectin is a glycoprotein of the hemopexin family which is synthesized and excreted by the liver, and abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the VTN gene.

<span class="mw-page-title-main">Bovine pancreatic ribonuclease</span>

Bovine pancreatic ribonuclease, also often referred to as bovine pancreatic ribonuclease A or simply RNase A, is a pancreatic ribonuclease enzyme that cleaves single-stranded RNA. Bovine pancreatic ribonuclease is one of the classic model systems of protein science. Two Nobel Prizes in Chemistry have been awarded in recognition of work on bovine pancreatic ribonuclease: in 1972, the Prize was awarded to Christian Anfinsen for his work on protein folding and to Stanford Moore and William Stein for their work on the relationship between the protein's structure and its chemical mechanism; in 1984, the Prize was awarded to Robert Bruce Merrifield for development of chemical synthesis of proteins.

Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is furin. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.

<span class="mw-page-title-main">Proprotein convertase 2</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such as the conversion of proinsulin to insulin intermediates. To generate the bioactive form of insulin, a second step involving the removal of C-terminal basic residues is required; this step is mediated by carboxypeptidases E and/or D. PC2 plays only a minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis compared to PC1. PC2 binds to the neuroendocrine protein named 7B2, and if this protein is not present, proPC2 cannot become enzymatically active. 7B2 accomplishes this by preventing the aggregation of proPC2 to inactivatable forms. The C-terminal domain of 7B2 also inhibits PC2 activity until it is cleaved into smaller inactive forms that lack carboxy-terminal basic residues. Thus, 7B2 is both an activator and an inhibitor of PC2. PC2 has been identified in a number of animals, including C. elegans.

<span class="mw-page-title-main">Cyclic peptide</span> Peptide chains which contain a circular sequence of bonds

Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side chain, for example in bacitracin; the carboxyl end and a side chain, for example in colistin; or two side chains or more complicated arrangements, for example in alpha-amanitin. Many cyclic peptides have been discovered in nature and many others have been synthesized in the laboratory. Their length ranges from just two amino acid residues to hundreds. In nature they are frequently antimicrobial or toxic; in medicine they have various applications, for example as antibiotics and immunosuppressive agents. Thin-Layer Chromatography (TLC) is a convenient method to detect cyclic peptides in crude extract from bio-mass.

<span class="mw-page-title-main">Insulin/IGF/Relaxin family</span> Group of proteins

The insulin/IGF/relaxin family is a group of evolutionary related proteins which possess a variety of hormonal activities. Family members in human include two subfamilies:

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additional peptide chains to certain ends, that makes hormone receptor binding sites located on its peptide hormone chain segments inaccessible. Prohormones can travel the blood stream as a hormone in an inactivated form, ready to be activated later in the cell by post-translational modification.

References

  1. ↑ "Entrez Gene: INS insulin".
  2. ↑ Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". Nature. 284 (5751): 26–32. Bibcode:1980Natur.284...26B. doi:10.1038/284026a0. PMID   6243748. S2CID   4363706.
  3. 1 2 3 4 "Interpretation for 80908 Proinsulin, Plasma". www.mayomedicallaboratories.com. Archived from the original on 2017-10-04. Retrieved 2017-03-09.
  4. ↑ Assali NS, Clark KE, Zugaib M, Brinkman CR, Nuwayhid B (1995). "Effects of estrogenic hormones on uteroplacental hemodynamics and progesterone production in the sheep". International Journal of Fertility. 23 (3): 219–23. PMC   8333766 . PMID   40897.
  5. ↑ Philipson LH, Bell G, Polonsky KS (January 2015). "Donald F. Steiner MD, 1930-2014: discoverer of proinsulin". Proceedings of the National Academy of Sciences of the United States of America. 112 (4): 940–1. Bibcode:2015PNAS..112..940P. doi: 10.1073/pnas.1423774112 . PMC   4313841 . PMID   25561547.
  6. ↑ Universal protein resource accession number P01308 for " INS_HUMAN" at UniProt.
  7. 1 2 3 4 5 Nolan C, Margoliash E, Peterson JD, Steiner DF (May 1971). "The structure of bovine proinsulin". The Journal of Biological Chemistry. 246 (9): 2780–95. doi: 10.1016/S0021-9258(18)62252-5 . PMID   4928892.
  8. 1 2 3 4 Snell CR, Smyth DG (August 1975). "Proinsulin: a proposed three-dimensional structure". The Journal of Biological Chemistry. 250 (16): 6291–5. doi: 10.1016/S0021-9258(19)41065-X . PMID   808541.
  9. 1 2 3 4 5 6 7 Weiss MA (July 2009). "Proinsulin and the genetics of diabetes mellitus". The Journal of Biological Chemistry. 284 (29): 19159–63. doi: 10.1074/jbc.R109.009936 . PMC   2740536 . PMID   19395706.
  10. 1 2 3 Yang Y, Hua QX, Liu J, Shimizu EH, Choquette MH, Mackin RB, Weiss MA (March 2010). "Solution structure of proinsulin: connecting domain flexibility and prohormone processing". The Journal of Biological Chemistry. 285 (11): 7847–51. doi: 10.1074/jbc.c109.084921 . PMC   2832934 . PMID   20106974.
  11. ↑ Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". Nature. 284 (5751): 26–32. Bibcode:1980Natur.284...26B. doi:10.1038/284026a0. PMID   6243748. S2CID   4363706.
  12. ↑ Groskreutz DJ, Sliwkowski MX, Gorman CM (February 1994). "Genetically engineered proinsulin constitutively processed and secreted as mature, active insulin" (PDF). The Journal of Biological Chemistry. 269 (8): 6241–5. doi: 10.1016/S0021-9258(17)37593-2 . PMID   8119968.
  13. 1 2 3 Kaufmann JE, Irminger JC, Halban PA (September 1995). "Sequence requirements for proinsulin processing at the B-chain/C-peptide junction". The Biochemical Journal. 310 (3): 869–74. doi:10.1042/bj3100869. PMC   1135976 . PMID   7575420.
  14. ↑ Wilson RM, Douglas CA, Tattersall RB, Reeves WG (September 1985). "Immunogenicity of highly purified bovine insulin: a comparison with conventional bovine and highly purified human insulins". Diabetologia. 28 (9): 667–70. doi: 10.1007/BF00291973 . PMID   3905477.
  15. ↑ Tanyolac S, Goldfine ID, Kroon L. "Insulin Pharmacology, Type of Regimens and Adjustments". Endotext.com. Archived from the original on 2011-07-25. Retrieved 2011-03-18.
  16. ↑ Home PD, Alberti KG (November 1982). "The new insulins. Their characteristics and clinical indications". Drugs. 24 (5): 401–13. doi:10.2165/00003495-198224050-00003. PMID   6756879. S2CID   28616749.
  17. ↑ Gray RS, Cowan P, di Mario U, Elton RA, Clarke BF, Duncan LJ (June 1985). "Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics". British Medical Journal. 290 (6483): 1687–91. doi:10.1136/bmj.290.6483.1687. PMC   1416075 . PMID   3924216.
  18. ↑ Mezza T, Ferraro PM, Sun VA, Moffa S, Cefalo CM, Quero G, et al. (November 2018). "Increased β-Cell Workload Modulates Proinsulin-to-Insulin Ratio in Humans". Diabetes. 67 (11): 2389–2396. doi:10.2337/db18-0279. hdl: 2434/587996 . PMID   30131390. S2CID   52058695.
  19. ↑ Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M (December 1997). "The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects". Diabetes. 46 (12): 1990–5. doi:10.2337/diab.46.12.1990. PMID   9392485. S2CID   44874023.
  20. 1 2 Hernández-Sánchez C, Mansilla A, de la Rosa EJ, de Pablo F (June 2006). "Proinsulin in development: New roles for an ancient prohormone". Diabetologia. 49 (6): 1142–50. doi: 10.1007/s00125-006-0232-5 . hdl: 10261/72608 . PMID   16596360.
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