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3.A.1.208.4
SUR1 sulfonylurea receptor; subunit and regulator of α-cell ATP-sensitive K+ channel (TC #1.A.2); determines ATP sensitivity; no inherent transport function known; associated with persistent hyperinsulinemic hypoglycemia of infancy due to focal adenomatous hyperplasia (also called ABCC8). Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) cause neonatal diabetes mellitus. Because mutant channels are inhibited less strongly by MgATP, this increases K(ATP) currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes (de Wet et al., 2007). Binds ligands (blockers): glibenclamide, tolbutamide, and meglitinide as well as agonists, SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide (Bessadok et al., 2011). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). Dominant missense mutations in ABCC9, promoting open channel formation, cause Cantú syndrome (Harakalova et al., 2012; van Bon et al., 2012). The N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2 (Pratt et al., 2011). Familial mild hyperglycemia is due to the ABCC8-V84I mutation (Gonsorcikova et al., 2011). ATP regulates KATP channels by promoting dimerization and conformational switching (Ortiz et al. 2013).  Mutations causing neonatal diabetes are attributed to alterations in the affinites for ATP and ADP (Ortiz and Bryan 2015).  Two groups of mutations with different cellular mechanisms have been identified. 1) Channel complexes with mutations in NBD2 of SUR1 traffic normally but are unable to be activated by MgADP. 2) Channel mutations in the TMS domains of SUR1 are retained in the ER and have variable functional impairment (Nessa et al. 2015). KATP channels (Kir6.2/SUR1) in the brain and endocrine pancreas  couple metabolic status to the membrane potential. In beta-cells, increases in cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively.  Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations.  Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015). SUR1 mutations constitute a genetic aetiology for neonatal diabetes, and they act by reducing the KATP channel's ATP sensitivity (Proks et al. 2006). Polymorphic ABCC8 isoforms are key regulatory proteins of cerebral oedema in many neurological disorders including traumatic brain injury (Jha et al. 2018). In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk while different variant polymorphisms are associated with favourable outcome, potentially suggesting distinct mechanisms (Jha et al. 2018).

Accession Number:Q09428
Protein Name:ACC8 aka SUR1 aka SUR aka ABCC8
Length:1581
Molecular Weight:177008.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:17
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Unknown

Cross database links:

Genevestigator: Q09428
eggNOG: prNOG04894
RefSeq: NP_000343.2   
Entrez Gene ID: 6833   
Pfam: PF00664    PF00005   
OMIM: 240800  phenotype
256450  phenotype
600509  gene
602485  phenotype
606176  phenotype
610374  phenotype
KEGG: hsa:6833   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005524 F:ATP binding
GO:0042626 F:ATPase activity, coupled to transmembrane m...
GO:0015079 F:potassium ion transmembrane transporter act...
GO:0008281 F:sulfonylurea receptor activity
GO:0005975 P:carbohydrate metabolic process
GO:0006813 P:potassium ion transport
GO:0055085 P:transmembrane transport

References (32)

[1] “Human chromosome 11 DNA sequence and analysis including novel gene identification.”  Taylor T.D.et.al.   16554811
[2] “Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.”  Thomas P.M.et.al.   7716548
[3] “Membrane topology of the amino-terminal region of the sulfonylurea receptor.”  Raab-Graham K.F.et.al.   10506167
[4] “Molecular biology of adenosine triphosphate-sensitive potassium channels.”  Aguilar-Bryan L.et.al.   10204114
[5] “Congenital hyperinsulinism: molecular basis of a heterogeneous disease.”  Meissner T.et.al.   10338089
[6] “Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy.”  Thomas P.M.et.al.   8751851
[7] “Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians.”  Inoue H.et.al.   8635661
[8] “Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews.”  Nestorowicz A.et.al.   8923011
[9] “Adenosine diphosphate as an intracellular regulator of insulin secretion.”  Nichols C.G.et.al.   8650576
[10] “Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM.”  Ohta Y.et.al.   9519757
[11] “Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene.”  Hansen T.et.al.   9568693
[12] “Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.”  Shyng S.-L.et.al.   9648840
[13] “Genetic heterogeneity in familial hyperinsulinism.”  Nestorowicz A.et.al.   9618169
[14] “Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.”  Verkarre V.et.al.   9769320
[15] “A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.”  Otonkoski T.et.al.   10334322
[16] “Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.”  Glaser B.et.al.   10447255
[17] “Clinical features of 52 neonates with hyperinsulinism.”  de Lonlay-Debeney P.et.al.   10202168
[18] “Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1.”  Tanizawa Y.et.al.   10615958
[19] “Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.”  Huopio H.et.al.   11018078
[20] “Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy.”  Cartier E.A.et.al.   11226335
[21] “Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels.”  Taschenberger G.et.al.   11867634
[22] “Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism.”  Huopio H.et.al.   12364426
[23] “Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor.”  Thornton P.S.et.al.   12941782
[24] “Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor.”  Magge S.N.et.al.   15356046
[25] “Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.”  Tornovsky S.et.al.   15579781
[26] “Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy.”  Ohkubo K.et.al.   15807877
[27] “Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.”  Henwood M.J.et.al.   15562009
[28] “A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.”  Proks P.et.al.   16613899
[29] “Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI).”  Fernandez-Marmiesse A.et.al.   16429405
[30] “Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.”  Suchi M.et.al.   16357843
[31] “Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.”  Babenko A.P.et.al.   16885549
[32] “Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers.”  Stanik J.et.al.   17213273

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FASTA formatted sequence
1:	MPLAFCGSEN HSAAYRVDQG VLNNGCFVDA LNVVPHVFLL FITFPILFIG WGSQSSKVHI 
61:	HHSTWLHFPG HNLRWILTFM LLFVLVCEIA EGILSDGVTE SHHLHLYMPA GMAFMAAVTS 
121:	VVYYHNIETS NFPKLLIALL VYWTLAFITK TIKFVKFLDH AIGFSQLRFC LTGLLVILYG 
181:	MLLLVEVNVI RVRRYIFFKT PREVKPPEDL QDLGVRFLQP FVNLLSKGTY WWMNAFIKTA 
241:	HKKPIDLRAI GKLPIAMRAL TNYQRLCEAF DAQVRKDIQG TQGARAIWQA LSHAFGRRLV 
301:	LSSTFRILAD LLGFAGPLCI FGIVDHLGKE NDVFQPKTQF LGVYFVSSQE FLANAYVLAV 
361:	LLFLALLLQR TFLQASYYVA IETGINLRGA IQTKIYNKIM HLSTSNLSMG EMTAGQICNL 
421:	VAIDTNQLMW FFFLCPNLWA MPVQIIVGVI LLYYILGVSA LIGAAVIILL APVQYFVATK 
481:	LSQAQRSTLE YSNERLKQTN EMLRGIKLLK LYAWENIFRT RVETTRRKEM TSLRAFAIYT 
541:	SISIFMNTAI PIAAVLITFV GHVSFFKEAD FSPSVAFASL SLFHILVTPL FLLSSVVRST 
601:	VKALVSVQKL SEFLSSAEIR EEQCAPHEPT PQGPASKYQA VPLRVVNRKR PAREDCRGLT 
661:	GPLQSLVPSA DGDADNCCVQ IMGGYFTWTP DGIPTLSNIT IRIPRGQLTM IVGQVGCGKS 
721:	SLLLAALGEM QKVSGAVFWS SLPDSEIGED PSPERETATD LDIRKRGPVA YASQKPWLLN 
781:	ATVEENIIFE SPFNKQRYKM VIEACSLQPD IDILPHGDQT QIGERGINLS GGQRQRISVA 
841:	RALYQHANVV FLDDPFSALD IHLSDHLMQA GILELLRDDK RTVVLVTHKL QYLPHADWII 
901:	AMKDGTIQRE GTLKDFQRSE CQLFEHWKTL MNRQDQELEK ETVTERKATE PPQGLSRAMS 
961:	SRDGLLQDEE EEEEEAAESE EDDNLSSMLH QRAEIPWRAC AKYLSSAGIL LLSLLVFSQL 
1021:	LKHMVLVAID YWLAKWTDSA LTLTPAARNC SLSQECTLDQ TVYAMVFTVL CSLGIVLCLV 
1081:	TSVTVEWTGL KVAKRLHRSL LNRIILAPMR FFETTPLGSI LNRFSSDCNT IDQHIPSTLE 
1141:	CLSRSTLLCV SALAVISYVT PVFLVALLPL AIVCYFIQKY FRVASRDLQQ LDDTTQLPLL 
1201:	SHFAETVEGL TTIRAFRYEA RFQQKLLEYT DSNNIASLFL TAANRWLEVR MEYIGACVVL 
1261:	IAAVTSISNS LHRELSAGLV GLGLTYALMV SNYLNWMVRN LADMELQLGA VKRIHGLLKT 
1321:	EAESYEGLLA PSLIPKNWPD QGKIQIQNLS VRYDSSLKPV LKHVNALISP GQKIGICGRT 
1381:	GSGKSSFSLA FFRMVDTFEG HIIIDGIDIA KLPLHTLRSR LSIILQDPVL FSGTIRFNLD 
1441:	PERKCSDSTL WEALEIAQLK LVVKALPGGL DAIITEGGEN FSQGQRQLFC LARAFVRKTS 
1501:	IFIMDEATAS IDMATENILQ KVVMTAFADR TVVTIAHRVH TILSADLVIV LKRGAILEFD 
1561:	KPEKLLSRKD SVFASFVRAD K