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The protein encoded by the ABCC8 ge
The protein encoded by the ABCC8 gene is a member of the ATP-binding cassette transporters. These proteins use energy in the form of ATP to drive the transport of various molecules across cell membranes. ABCC8 belongs to a subfamily of transporters that contains the chloride channel that is mutated in cystic fibrosis (CFTR) and also the proteins that are involved in multi-drug resistance.
Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily
The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas (1). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin.
The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.
The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.
Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.
Molecular Information
ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.
By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).
Figure 1. Location of ABCC8 on the human genome.
Figure 1
Location of ABCC8 on the human genome.
ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)
The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).
The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.
As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.
The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.
Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).
Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2
SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles
For a more complete list of research articles on ABCC8 and diabetes, search PubMed.
The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).
A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).
A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).
Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).
Link Roundup for ABCC8
Live Searches
Diabetes and ABCC8 in PubMed | PubMed Central | Books
Background Information
ABCC8 in OMIM
The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf
Molecular Biology
ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene
Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily
The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas (1). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin.
The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.
The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.
Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.
Molecular Information
ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.
By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).
Figure 1. Location of ABCC8 on the human genome.
Figure 1
Location of ABCC8 on the human genome.
ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)
The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).
The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.
As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.
The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.
Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).
Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2
SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles
For a more complete list of research articles on ABCC8 and diabetes, search PubMed.
The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).
A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).
A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).
Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).
Link Roundup for ABCC8
Live Searches
Diabetes and ABCC8 in PubMed | PubMed Central | Books
Background Information
ABCC8 in OMIM
The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf
Molecular Biology
ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene
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The protein encoded by the ABCC8 gene is a member of the ATP-binding cassette transporters. These proteins use energy in the form of ATP to drive the transport of various molecules across cell membranes. ABCC8 belongs to a subfamily of transporters that contains the chloride channel that is mutated in cystic fibrosis (CFTR) and also the proteins that are involved in multi-drug resistance.
Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily
The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas (1). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin.
The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.
The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.
Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.
Molecular Information
ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.
By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).
Figure 1. Location of ABCC8 on the human genome.
Figure 1
Location of ABCC8 on the human genome.
ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)
The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).
The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.
As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.
The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.
Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).
Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2
SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles
For a more complete list of research articles on ABCC8 and diabetes, search PubMed.
The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).
A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).
A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).
Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).
Link Roundup for ABCC8
Live Searches
Diabetes and ABCC8 in PubMed | PubMed Central | Books
Background Information
ABCC8 in OMIM
The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf
Molecular Biology
ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene
Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily
The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas (1). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin.
The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels.
The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins.
Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.
Molecular Information
ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat.
By fluorescence in situ hybridization, it was found that the ABBC8 gene maps to the short arm of chromosome 11 (Figure 1) (5). It has 41 exons (coding regions) that span over 84,000 bases (see evidence).
Figure 1. Location of ABCC8 on the human genome.
Figure 1
Location of ABCC8 on the human genome.
ABCC8 maps to chromosome 11, approximately between 17,370 and 17,470 kilobases (kb). Click Image maplink.jpg or here for a current and interactive view of the location of ABCC8 in the human genome. Note: this figure was (more...)
The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains (view domains).
The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity.
As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated (7). In addition, ABC genes also contain a signature C motif.
The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane.
Several single nucleotide polymorphisms (SNPs) have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein (Figure 2). However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change (see below).
Figure 2. SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
Figure 2
SNP positions of ABCC8 mapped to the 3D structure of a multidrug resistance ABC transporter homolog in Vibrio cholera.
The figure shows the positions of non-synonymous amino acid changes (green residues) caused by SNPs in the coding sequence. (more...)
ABCC8 and Diabetes: Digest of Recent Articles
For a more complete list of research articles on ABCC8 and diabetes, search PubMed.
The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes (8).
A mutation in ABCC8 was observed to cause an extremely rare form of diabetes, autosomal dominant diabetes, in a Finnish family (9). The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes (10).
A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but this still codes for the residue arginine (R1273R). The normal and mutant alleles were called G and A, respectively. Among non-diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wild-type (GG). Because type 2 diabetes is more common in Mexican Americans than in the general US population, it has been proposed that individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin (11).
Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes (12).
Link Roundup for ABCC8
Live Searches
Diabetes and ABCC8 in PubMed | PubMed Central | Books
Background Information
ABCC8 in OMIM
The Human ATP-Binding Cassette (ABC) Transporter Superfamily on the Bookshelf
Molecular Biology
ABCC8 in Entrez Gene | Evidence Viewer | Map Viewer | Domains: Transmembrane region 1, ATPase 1, Transmembrane domain 2, ATPase 2 | SNPs | BLink | HomoloGene
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Protein yang dikode oleh gen ABCC8 adalah anggota dari transporter kaset ATP mengikat. Protein ini menggunakan energi dalam bentuk ATP untuk mendorong pengangkutan berbagai molekul melintasi membran sel. ABCC8 milik subfamili transporter yang berisi saluran klorida yang bermutasi pada cystic fibrosis (CFTR) dan juga protein yang terlibat dalam resistensi multi-obat. Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamili ABCC8 The protein juga dikenal sebagai reseptor urea sulfonylurea (SUR). SUR adalah salah satu protein yang menyusun saluran kalium ATP-sensitif (channel KATP) ditemukan di pankreas (1). Protein lain, yang disebut Kir6.2, membentuk inti dari saluran dan dikodekan oleh gen KCNJ11. Saluran KATP memainkan peran sentral dalam sekresi insulin yang diinduksi glukosa dengan menghubungkan sinyal yang berasal dari metabolisme glukosa (kenaikan ATP) membran depolarisasi (karena saluran KATP penutupan) dan sekresi insulin. Kegiatan saluran KATP mengatur rilis insulin. Sulfonilurea adalah obat yang dapat memodulasi aktivitas saluran KATP dan digunakan dalam pengobatan diabetes tipe 2. Dengan mengikat SUR, mereka menghambat saluran dan merangsang pelepasan insulin. Hal ini menyebabkan penurunan kadar glukosa darah. Kegiatan saluran KATP juga diatur oleh subtipe SUR (SUR, juga dikenal sebagai SUR1, dikodekan oleh ABCC8, atau SUR2A dan SUR2B, yang dikodekan oleh ABCC9). Dalam pankreas, sebagian besar saluran KATP dianggap kompleks empat protein SUR1 dan empat protein Kir6.2. Mutasi baik ABCC8 atau KCNJ11 dapat mengakibatkan up-diatur sekresi insulin, keadaan ini disebut familial hipoglikemia hiperinsulinemia gigih bayi (PHHI ) (2-4). Variasi genetik di ABCC8 juga telah terlibat dalam rilis gangguan insulin yang terlihat dalam tipe 2 diabetes. Molecular Informasi gen ABC ditemukan di banyak spesies eukariotik yang berbeda dan sangat kekal antara spesies, menunjukkan bahwa banyak gen tersebut ada di awal eukariotik evolusi. Sebuah pencarian BLAST menggunakan ABCC8 manusia sebagai query menemukan protein dalam 30 spesies yang berbeda, yang meliputi organisme multiseluler (metazoa), jamur, dan tanaman. Potensi gen homolog benar telah diidentifikasi dalam mouse dan tikus. Dengan fluoresensi hibridisasi in situ, ditemukan bahwa peta gen ABBC8 ke lengan pendek kromosom 11 (Gambar 1) (5). Memiliki 41 ekson (daerah pengkode) yang mencakup lebih dari 84.000 basis (lihat bukti). Gambar 1. Lokasi ABCC8 pada genom manusia. Gambar 1 Lokasi ABCC8 pada genom manusia. peta ABCC8 pada kromosom 11, kira-kira antara 17.370 dan 17.470 kilobases (kb). Klik Gambar maplink.jpg atau di sini untuk melihat saat ini dan interaktif dari lokasi ABCC8 dalam genom manusia. Catatan: angka ini (more ...) . Protein transporter ABC, seperti ABCC8, biasanya berisi dua domain ATP-mengikat dan dua domain transmembran (lihat domain) Domain ATP-binding juga dikenal sebagai nukleotida lipatan mengikat (NBFs ), dan mutasi baik NBF1 atau NBF2 dapat menyebabkan PHHI (6). Hal ini menunjukkan bahwa kedua NBF daerah SUR yang diperlukan untuk pengaturan normal aktivitas saluran KATP. Seperti yang ditemukan di semua protein yang mengikat ATP, domain mengikat nukleotida dari keluarga ABC protein mengandung motif khas yang disebut Walker A dan B. Walker Sebuah motif mengandung residu lisin yang sangat penting untuk mengaktifkan saluran KATP. Ketika residu lisin ini bermutasi di NBF1, tetapi tidak NBF2, saluran KATP tidak lagi dapat diaktifkan (7). Selain itu, gen ABC juga mengandung motif signature C. Domain transmembran mengandung 6-11 membran mencakup heliks, dan protein ABCC mengandung 6. heliks ini menyediakan protein dengan spesifisitas untuk molekul mereka transportasi melintasi membran. Beberapa polimorfisme nukleotida tunggal (SNP) telah ditemukan dalam gen ABCC8. Biasanya SNP terkait dengan penyakit terjadi dalam coding daerah (ekson) dari gen, dan mereka menghasilkan perubahan asam amino non-identik. Di ABCC8, ada tujuh SNP tersebut (pada saat penulisan) yang menyebabkan perpindahan asam amino dalam protein matang (Gambar 2). Namun, salah satu SNP gen ABCC8 yang telah dikaitkan dengan diabetes (R1273R) tidak menyebabkan perubahan asam amino (lihat di bawah). Gambar 2. Posisi SNP dari ABCC8 dipetakan ke struktur 3D dari resistensi multidrug ABC transporter homolog di Vibrio cholera. Gambar 2 posisi SNP dari ABCC8 dipetakan ke struktur 3D dari resistensi multidrug ABC transporter homolog di Vibrio cholera. Angka ini menunjukkan posisi perubahan asam amino non-identik (residu hijau) yang disebabkan oleh SNP di urutan coding. (More ...) ABCC8 dan Diabetes: Digest Anggaran Terbaru Untuk daftar yang lebih lengkap artikel penelitian tentang ABCC8 dan diabetes, mencari PubMed. Dua gen yang mengkode saluran KATP, ABBC8 dan KCNJ11, berada berdekatan satu sama lain pada kromosom 11. Sebuah varian dari ABCC8, disebut A1369S, dalam linkage disequilibrium hampir lengkap dengan varian KCNJ11 disebut E23K. Ini berarti bahwa dari bukti genetik, sulit untuk menentukan apakah itu adalah varian A1369S atau varian E23K yang predisposes untuk diabetes tipe 2 (8). Sebuah mutasi di ABCC8 diamati menyebabkan bentuk yang sangat langka diabetes, autosomal dominan diabetes, dalam sebuah keluarga Finlandia (9). Saklar glutamat untuk lisin pada residu 1506 (E1506K) dalam protein SUR1 menyebabkan hiperinsulinemia bawaan. Mutasi mengurangi aktivitas saluran KATP, meningkatkan sekresi insulin. Masa dewasa awal, kemampuan sel-sel beta untuk mengeluarkan jumlah yang cukup insulin kelelahan, yang menyebabkan diabetes (10). Varian diam di ekson 31 gen ABCC8 telah dikaitkan dengan konsentrasi tinggi insulin non-diabetes Meksiko Amerika . Kodon Agg bermutasi ke AGA, tapi ini masih kode untuk arginin residu (R1273R). Normal dan mutan alel disebut G dan A masing-masing. Di antara non-penderita diabetes, mereka yang homozigot untuk alel mutan (AA genotipe) memiliki kadar insulin saat puasa, dibandingkan dengan heterozigot (AG) dan normal wild type (GG). Karena diabetes tipe 2 lebih sering terjadi pada orang Amerika Meksiko daripada populasi umum di AS, telah diusulkan bahwa individu dengan genotipe AA berada pada risiko yang lebih tinggi dari diabetes karena over-sekresi insulin (11). Dua polimorfisme umum gen ABCC8 (ekson 16-3t / c dan ekson 18 T / C) telah bervariasi dikaitkan dengan diabetes tipe 2. Namun, sebuah studi kasus kontrol besar baru-baru di Inggris mengungkapkan bahwa varian ABCC8 ini tampaknya tidak terkait dengan diabetes (12). link Roundup untuk ABCC8 Hidup pencarian Diabetes dan ABCC8 di PubMed | PubMed Central | Buku Latar Belakang Informasi ABCC8 di OMIM Manusia ATP-Binding Cassette (ABC) Transporter Superfamili di Bookshelf Biologi Molekuler ABCC8 di Entrez Gene | Bukti Viewer | Peta Viewer | Domain: daerah transmembran 1, ATPase 1, transmembran domain 2, ATPase 2 | SNP | Blink | HomoloGene
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