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36-402: 1BYW , 1UJL , 2L0W , 2L1M , 2L4R , 2LE7 , 4HP9 , 4HQA , 2N7G 3757 16511 ENSG00000055118 ENSMUSG00000038319 Q12809 O35219 NM_000238 NM_001204798 NM_172056 NM_172057 NM_001294162 NM_013569 NP_000229 NP_001191727 NP_742053 NP_742054 NP_001281091 NP_038597 hERG (the h uman E ther-à-go-go - R elated G ene)

72-434: A gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms. Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to orthologous —or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with

108-422: A protein complex may be identical, homologous or totally dissimilar and dedicated to disparate tasks. In some protein assemblies, one subunit may be a "catalytic subunit" that enzymatically catalyzes a reaction, whereas a "regulatory subunit" will facilitate or inhibit the activity. Although telomerase has telomerase reverse transcriptase as a catalytic subunit, regulation is accomplished by factors outside

144-458: Is a gene ( KCNH2 ) that codes for a protein known as K v 11.1 , the alpha subunit of a potassium ion channel . This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to the electrical activity of the heart : the hERG channel mediates the repolarizing I Kr current in the cardiac action potential , which helps coordinate the heart's beating. When this channel's ability to conduct electrical current across

180-526: Is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings , variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. (For that, see Proteoforms .) Through RNA splicing mechanisms, mRNA has

216-443: Is a symmetrical arrangement of two identical α-globin subunits and two identical β-globin subunits. Longer multimeric proteins such as microtubules and other cytoskeleton proteins may consist of very large numbers of subunits. For example, dynein is a multimeric protein complex involving two heavy chains (DHCs), two intermediate chains (ICs), two light-intermediate chains (LICs) and several light chains (LCs). The subunits of

252-456: Is indicated by a subscript. For example, ATP synthase has a type of subunit called α. Three of these are present in the ATP synthase molecule, leading to the designation α 3 . Larger groups of subunits can also be specified, like α 3 β 3 -hexamer and c-ring. Naturally occurring proteins that have a relatively small number of subunits are referred to as oligomeric . For example, hemoglobin

288-532: Is no conclusive evidence that it acts primarily by producing novel protein isoforms. Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of

324-543: Is often used as a proxy for the abundance of protein isoforms, though proteomics experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there

360-692: Is the main post-transcriptional modification process that produces mRNA transcript isoforms, and is a major molecular mechanism that may contribute to protein diversity. The spliceosome , a large ribonucleoprotein , is the molecular machine inside the nucleus responsible for RNA cleavage and ligation , removing non-protein coding segments ( introns ). Because splicing is a process that occurs between transcription and translation , its primary effects have mainly been studied through genomics techniques—for example, microarray analyses and RNA sequencing have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance

396-541: Is very similar to that contained in bacterial KcsA channels . Although a full crystal structure for hERG is not yet available, a structure has been found for the cytoplasmic N-terminus, which was shown to contain a PAS domain (aminoacid 26–135) that slows the rate of deactivation. Loss-of-function mutations in this channel may lead to long QT syndrome (LQT2), while gain-of-function mutations may lead to short QT syndrome . Both clinical disorders stem from ion channel dysfunction (so-called channelopathies ) that can lead to

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432-507: The 5' AMP-activated protein kinase (AMPK), an enzyme, which performs different roles in human cells, has 3 subunits: In human skeletal muscle, the preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1. The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as mutations and polymorphisms are sometimes also considered distinct isoforms. Alternative splicing

468-530: The Ether-à-go-go gene are anaesthetised with ether , their legs start to shake, like the dancing at the then popular Whisky a Go Go nightclub in West Hollywood, California . HERG has been shown to interact with the 14-3-3 epsilon protein, encoded by YWHAE . Protein subunit A subunit is often named with a Greek or Roman letter, and the numbers of this type of subunit in a protein

504-494: The S5 and S6 helices, there is an extracellular loop (known as 'the turret') and 'the pore loop', which begins and ends extracellularly but loops into the plasma membrane; the pore loop for each of the hERG subunits in one channel faces into the ion-conducting pore and is adjacent to the corresponding loops of the three other subunits, and together they form the selectivity filter region of the channel pore. The selectivity sequence, SVGFG,

540-456: The ability to select different protein-coding segments ( exons ) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein. The discovery of isoforms could explain the discrepancy between the small number of protein coding regions of genes revealed by the human genome project and the large diversity of proteins seen in an organism: different proteins encoded by

576-491: The canonical sequence. However, some isoforms show much greater divergence (for example, through trans-splicing ), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all

612-504: The cardiac 'rapid' delayed rectifier current ( I Kr ), including I Kr 's inward rectification that results in the channel producing a 'paradoxical resurgent current' in response to repolarization of the membrane. A detailed atomic structure for hERG based on X-ray crystallography is not yet available, but structures have recently been solved by electron microscopy. In the laboratory the heterologously expressed hERG potassium channel comprises four identical alpha subunits, which form

648-408: The cell membrane is inhibited or compromised, either by application of drugs or by rare mutations in some families, it can result in a potentially fatal disorder called long QT syndrome . Conversely, genetic mutations that increase the current through these channels can lead to the related inherited heart rhythm disorder short QT syndrome . A number of clinically successful drugs in the market have had

684-533: The channel's pore through the plasma membrane . Each hERG subunit consists of 6 transmembrane alpha helices , numbered S1-S6, a pore helix situated between S5 and S6, and cytoplasmically located N- and C-termini . The S4 helix contains a positively charged arginine or lysine amino acid residue at every 3rd position and is thought to act as a voltage-sensitive sensor, which allows the channel to respond to voltage changes by changing conformations between conducting and non-conducting states (called 'gating'). Between

720-427: The controversy as to whether the channels conducting I Kr include other subunits (e.g., beta subunits) or whether the channels include a mixture of different types ( isoforms ) of hERG, but, when the originally-discovered form of hERG is experimentally transferred into cells that previously lacked hERG (i.e., heterologous expression), a potassium ion channel is formed, and this channel has many signature features of

756-486: The different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant. Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell ( RNA polymerase , transcription factors , and other enzymes ) begin transcription at different promoters—the region of DNA near

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792-415: The drugs that can cause QT prolongation, the more common ones include antiarrhythmics (especially Class 1A and Class III), anti-psychotic agents, and certain antibiotics (including quinolones and macrolides). Although there exist other potential targets for cardiac adverse effects, the vast majority of drugs associated with acquired QT prolongation are known to interact with the hERG potassium channel. One of

828-464: The function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions. A glycoform is an isoform of a protein that differs only with respect to the number or type of attached glycan . Glycoproteins often consist of a number of different glycoforms, with alterations in the attached saccharide or oligosaccharide . These modifications may result from differences in biosynthesis during

864-413: The isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells in vitro , it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because

900-501: The main reasons for this phenomenon is the larger inner vestibule of the hERG channel, thus providing more space for many different drug classes to bind and block this potassium channel. hERG containing channels are blocked by amiodarone , and it does prolong the QT interval, but its multiple other antiarrhythmic effects prevent this from causing torsades de pointes. Thioridazine causes peculiarly severe QTc prolongation by blocking hERG and

936-422: The major portion of one of the ion channel proteins (the 'rapid' delayed rectifier current ( I Kr )) that conducts potassium (K) ions out of the muscle cells of the heart ( cardiac myocytes ), and this current is critical in correctly timing the return to the resting state ( repolarization ) of the cell membrane during the cardiac action potential. Sometimes, when referring to the pharmacological effects of drugs,

972-404: The process of glycosylation , or due to the action of glycosidases or glycosyltransferases . Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with lectins , as in lectin affinity chromatography and lectin affinity electrophoresis . Typical examples of glycoproteins consisting of glycoforms are

1008-483: The protein. An enzyme composed of both regulatory and catalytic subunits when assembled is often referred to as a holoenzyme . For example, class I phosphoinositide 3-kinase is composed of a p110 catalytic subunit and a p85 regulatory subunit. One subunit is made of one polypeptide chain. A polypeptide chain has one gene coding for it – meaning that a protein must have one gene for each unique subunit. Isoform A protein isoform , or " protein variant ",

1044-458: The risk of potentially fatal cardiac arrhythmias (e.g., torsades de pointes ), due to repolarization disturbances of the cardiac action potential. There are far more hERG mutations described for long QT syndrome than for short QT syndrome. This channel is also sensitive to drug binding, as well as decreased extracellular potassium levels, both of which can result in decreased channel function and drug-induced (acquired) long QT syndrome . Among

1080-472: The same gene could increase the diversity of the proteome . Isoforms at the RNA level are readily characterized by cDNA transcript studies. Many human genes possess confirmed alternative splicing isoforms. It has been estimated that ~100,000 expressed sequence tags ( ESTs ) can be identified in humans. Isoforms at the protein level can manifest in the deletion of whole domains or shorter loops, usually located on

1116-438: The structure of most isoforms in the human proteome has been predicted by AlphaFold and publicly released at isoform.io . The specificity of translated isoforms is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms. For example,

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1152-565: The surface of the protein. One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the alternative splicing of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as the abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine which, if any, isoforms represent functional protein products, and

1188-470: The tendency to inhibit hERG, lengthening the QT and potentially leading to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia called torsades de pointes ). This has made hERG inhibition an important antitarget that must be avoided during drug development. hERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells. hERG forms

1224-450: The terms "hERG channels" and I Kr are used interchangeably, but, in the technical sense, "hERG channels" can be made only by scientists in the laboratory; in formal terms, the naturally occurring channels in the body that include hERG are referred to by the name of the electrical current that has been measured in that cell type, so, for example, in the heart, the correct name is I Kr . This difference in nomenclature becomes clearer in

1260-619: Was first named and described in a paper by Jeff Warmke and Barry Ganetzky, then both at the University of Wisconsin–Madison . The hERG gene is the human homolog of the Ether-à-go-go gene found in the Drosophila fly; Ether-à-go-go was named in the 1960s by William D. Kaplan and William E. Trout, III, while at the City of Hope Hospital in Duarte, California . When flies with mutations in

1296-728: Was withdrawn by the manufacturer for this reason. Due to the documented potential of QT-interval-prolonging drugs, the United States Food and Drug Administration issued recommendations for the establishment of a cardiac safety profile during pre-clinical drug development: ICH S7B. The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, issued as CHMP/ICH/423/02, adopted by CHMP in May 2005. Preclinical hERG studies should be accomplished in GLP environment. The hERG gene

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