Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures

Martin, Gregory M.; Sung, Min Woo; Shyng, Show Ling

doi:10.1016/j.mce.2019.110667

Cited by 28 publications

(34 citation statements)

References 86 publications

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“…ABC proteins transport various molecules (based on the Entrez gene summary for ABCC8 gene). The research findings of Martin et al 15 show that the protein encoded by ABCC8 plays a role in regulating the ATP-sensitive potassium (K-ATP) channel and insulin release. The ATP sensitive potassium channel is a protein complex that can couple the cell energy level with cell excitability and control a wide range of physiological processes, including hormone secretion, neuronal transmission, vasodilation, and cardiac and neuron pretreatment for ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

ABCC8 mRNA expression is an independent prognostic factor for glioma and can predict chemosensitivity

Zhou

Liu

Zhao

et al. 2020

Sci Rep

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Glioma is the most common primary intracranial tumor and is associated with very low survival rates. The development of reliable biomarkers can help to elucidate the molecular mechanisms involved in glioma development. Here the expression of ABCC8 mRNA, clinical characteristics, and survival information based on 1893 glioma samples from four independent databases were analyzed. The expression patterns of ABCC8 mRNA were compared by a Chi square test. The overall survival rate of gliomas was evaluated according to the expression level of ABCC8 mRNA. The prognostic value of this marker in gliomas was tested using Cox single factor and multi factor regression analyses. We found patients with low WHO grade, oligodendrocytoma, low molecular grade, IDH mutation, and 1p19q combined deletion had high ABCC8 mRNA expression. The patients with high expression of ABCC8 mRNA had longer survival. ABCC8 mRNA expression was a new independent prognostic index for glioma. Temozolomide chemotherapy was an independent index to prolong overall survival in high ABCC8 mRNA expression glioma patients, whereas in patients with low expression, there was no significant difference. So ABCC8 mRNA expression could be an independent prognostic indicator for glioma patients and could predict the sensitivity of glioma to temozolomide.

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Section: Discussionmentioning

confidence: 99%

ABCC8 mRNA expression is an independent prognostic factor for glioma and can predict chemosensitivity

Zhou

Liu

Zhao

et al. 2020

Sci Rep

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“…The repression of Kir6.2/SUR1 channels stimulates the release of insulin [60], and it has been reported that mutations and deficiencies of ABCC8 and KCNJ11 induce hyperinsulinism [61][62][63][64][65]. In various studies and clinical reports, the hypersecretion of insulin has been linked to the development of several types of cancer, including breast, colon, liver, and kidney cancers [66,67], and the survival rates through GEPIA in our research also confirmed that higher the expression levels of the two genes, the better is the survival rate ( Figure S4A).…”

Section: Discussionmentioning

confidence: 99%

CeRNA Network Analysis Representing Characteristics of Different Tumor Environments Based on 1p/19q Codeletion in Oligodendrogliomas

Ahn

Park

Kang

et al. 2020

Cancers

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Oligodendroglioma (OD) is a subtype of glioma occurring in the central nervous system. The 1p/19q codeletion is a prognostic marker of OD with an isocitrate dehydrogenase (IDH) mutation and is associated with a clinically favorable overall survival (OS); however, the exact underlying mechanism remains unclear. Long non-coding RNAs (lncRNAs) have recently been suggested to regulate carcinogenesis and prognosis in cancer patients. Here, we performed in silico analyses using low-grade gliomas from datasets obtained from The Cancer Genome Atlas to investigate the effects of ceRNA with 1p/19q codeletion on ODs. Thus, we selected modules of differentially expressed genes that were closely related to 1p/19q codeletion traits using weighted gene co-expression network analysis and constructed 16 coding RNA–miRNA–lncRNA networks. The ceRNA network participated in ion channel activity, insulin secretion, and collagen network and extracellular matrix (ECM) changes. In conclusion, ceRNAs with a 1p/19q codeletion can create different tumor microenvironments via potassium ion channels and ECM composition changes; furthermore, differences in OS may occur. Moreover, if extrapolated to gliomas, our results can provide insights into the consequences of identical gene expression, indicating the possibility of tracking different biological processes in different subtypes of glioma.

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“…While most residues in loop 6 are not resolved in the structure, it is possible that this loop interacts transiently with TMD0 and that these interactions change upon proteolytic digestion. In support of this hypothesis, loop 6 in SUR1 contacts TMD0 in some KATP channel structures (18,38), but is not observed in other KATP channel structures (19,20,39), likely due to flexibility. On the cytoplasmic side of the membrane, there is a network of interactions formed by TM4 and TM5 in TMD0, the membrane-embedded portion of the L0 lasso structure, the L0 amphipathic helix, and residues in TM6, TM7, TM15, and TM16 in TM bundle 1 ( Fig.…”

Section: High-resolution Structure Of Tmd0 and The L0 Linkermentioning

confidence: 82%

“…Comparison of the TMD0 structures from Ycf1p, MRP1 22, and SUR1 (38) shows that the domain adopts the same fold in all three proteins (Fig. 2B, (19,20).…”

Section: Variable Association With the Abc Core Suggests How Tmd0 Modmentioning

confidence: 99%

“…High-resolution structural information for TMD0 is available only for the atypical ABCC protein SUR1 (19,20), which is part of the large hetero-octameric ATP-sensitive K+ (KATP) channel complex. In contrast, structures of monomeric ABC transporters showed only lowresolution density for TMD0 that was insufficient for building a full atomic model or lacked density for the domain altogether (14,(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory R region of ABCC transporters

Bickers

Rubinstein

Kanelis

2021

Preprint

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ATP binding cassette (ABC) proteins typically function in active transport of solutes across membranes. The ABC core structure is comprised of two transmembrane domains (TMD1 and TMD2) and two cytosolic nucleotide binding domains (NBD1 and NBD2). Some members of the C-subfamily of ABC (ABCC) proteins, including human multidrug resistance proteins (MRPs), also possess an N-terminal transmembrane domain (TMD0) that contains five transmembrane α-helices and is connected to the ABC core by the L0 linker. While TMD0 was resolved in SUR1, the atypical ABCC protein that is part of the hetero-octameric ATP-sensitive K+ channel, little is known about the structure of TMD0 in monomeric ABC transporters. Here, we present the structure of yeast cadmium factor 1 protein (Ycf1p), a homologue of human MRP1, determined by electron cryomicroscopy (cryo-EM). Comparison of Ycf1p, SUR1, and a structure of MRP1 that showed TMD0 at low resolution demonstrates that TMD0 can adopt different orientations relative to the ABC core, including a 145° rotation between Ycf1p and SUR1. The cryo-EM map also reveals that segments of the regulatory (R) region, which links NBD1 to TMD2 and was poorly resolved in earlier ABCC structures, interacts with the L0 linker, NBD1, and TMD2. These interactions, combined with fluorescence quenching experiments of isolated NBD1 with and without the R region, suggests how post-translational modifications of the R region modulate ABC protein activity. Mapping known mutations from MRP2 and MRP6 onto the Ycf1p structure explains how mutations involving TMD0 and the R region of these proteins lead to disease.Statement of SignificanceThe Ycf1p structure provides an atomic model for the TMD0 domain of ABCC transporters and for two segments of the regulatory (R) region that links NBD1 to TMD2. The orientation of TMD0 in Ycf1p differs from that seen in SUR1, the regulatory ABCC protein in KATP channels, demonstrating flexibility in TMD0/ABC core contacts. The structure suggests how post-translational modifications of the R region modulate ABC protein activity and provides a mechanistic understanding of several diseases that occur due to mutation of human homologues of Ycf1p.

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Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures

Cited by 28 publications

References 86 publications

ABCC8 mRNA expression is an independent prognostic factor for glioma and can predict chemosensitivity

ABCC8 mRNA expression is an independent prognostic factor for glioma and can predict chemosensitivity

CeRNA Network Analysis Representing Characteristics of Different Tumor Environments Based on 1p/19q Codeletion in Oligodendrogliomas

Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory R region of ABCC transporters

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