The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides

Tsirigos, Konstantinos D.; Peters, Christoph; Shu, Nanjiang; Käll, Lukas; Elofsson, Arne

doi:10.1093/nar/gkv485

Cited by 838 publications

(766 citation statements)

References 45 publications

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“…The sequence alignment produced by HHpred covers the five transmembrane segments (TMSs) that are conserved between all of these structures and which, after dimerization, make up the core of the transporter. The predicted positions of these TMSs in BilEB closely match topology predictions made using the TOPCONS server [35] (Figure 1E). The additional sixth TMS, predicted by TOPCONS, would position the predicted C-terminal SBD at the outer surface of the membrane where it could serve as receptor and bind ligands for subsequent transport.…”

Section: Sequence Analysissupporting

confidence: 72%

“…Sequences are shaded according to percentage sequence similarity. Bars above the alignment indicate transmembrane segments (TMSs) predicted by TOPCONS [35] (light green) or by comparison to crystal structures of homologous ABC importers (dark green). Lettering indicates the orientation of predicted TMSs relative to the cytoplasm (out-to-in or in-to-out), which is in agreement between the two methods.…”

Section: Sequence Analysismentioning

confidence: 99%

“…The reference sequence for the cluster containing PsOpuCC was removed during an automated trimming step. Topology predictions made by TOPCONS [35] are shown in green (TMSs) and purple (signal sequences). Orange indicates an additional SBP fold as predicted by HHpred [36].…”

Section: Conservation Of Bilebmentioning

confidence: 99%

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Crystal Structure of the Substrate-Binding Domain from Listeria monocytogenes Bile-Resistance Determinant BilE

2016

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BilE has been reported as a bile resistance determinant that plays an important role in colonization of the gastrointestinal tract by Listeria monocytogenes, the causative agent of listeriosis. The mechanism(s) by which BilE mediates bile resistance are unknown. BilE shares significant sequence similarity with ATP-binding cassette (ABC) importers that contribute to virulence and stress responses by importing quaternary ammonium compounds that act as compatible solutes. Assays using related compounds have failed to demonstrate transport mediated by BilE. The putative substrate-binding domain (SBD) of BilE was expressed in isolation and the crystal structure solved at 1.5 Å. Although the overall fold is characteristic of SBDs, the binding site varies considerably relative to the well-characterized homologs ProX from Archaeoglobus fulgidus and OpuBC and OpuCC from Bacillus subtilis. This suggests that BilE may bind an as-yet unknown ligand. Elucidation of the natural substrate of BilE could reveal a novel bile resistance mechanism.

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Section: Sequence Analysissupporting

confidence: 72%

Section: Sequence Analysismentioning

confidence: 99%

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Crystal Structure of the Substrate-Binding Domain from Listeria monocytogenes Bile-Resistance Determinant BilE

2016

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“…To analyze the effects of the mutations on the TMD, we submitted the different sequences to the TOPCONS server, which predicts the location and stability of transmembrane domains (46). The predicted outcomes show only minor changes in the location of the transmembrane helix (Ϯ2 amino acids (Fig.…”

Section: Sequence Conservation Of Tmds and Their Surroundings-mentioning

confidence: 99%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

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Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of 100°and a translation of 1.5 Å per added residue. Surprisingly, the added alanines had little effect on the binding affinity of IFN to the cell surface receptors, STAT phosphorylation, or gene induction. Similarly, substitution of the juxtamembrane residues of the TMD with alanines, or replacement of the TMD of IFNAR1 with that of IFNAR2, did not affect IFN binding or activity. Finally, only the addition of 10 serine residues (but not 2 or 4) between the extracellular domain of IFNAR1 and the TMD had some effect on signaling. Bioinformatic analysis shows a correlation between high sequence conservation of TMDs of cytokine receptors and the ability to transmit structural signals. Sequence conservation near the TMD of IFNAR1 is low, suggesting limited functional importance for this region. Our results suggest that IFN binding to the extracellular domains of IFNAR1 and IFNAR2 promotes proximity between the intracellular domains and that differential signaling is a function of duration of activation and affinity of binding rather than specific conformational changes transmitted from the outside to the inside of the cell.Type I interferons (IFNs) orchestrate the antiviral innate immunity in vertebrates. They consist of 16 members in humans as follows: 12 different IFN␣ subtypes, as well as IFN␤, IFN, IFN⑀, and IFN. They are clustered on the short arm of chromosome 9. All type I interferons elicit their innate and adaptive immune responses after binding to the receptor and forming the IFNAR1-IFN-IFNAR2 ternary complex (1, 2), the formation of which is essential for signaling. Both IFNAR1 and IFNAR2 belong to the class II helical cytokine receptors with four fibronectin type III-like subdomains for IFNAR1 and two subdomains for IFNAR2. The extracellular domains are followed by a single helix of 21 amino acids spanning the membrane, which in turn is connected to mostly natively unstructured intracellular domains and their associated effectors (Fig. 1A) (3). Cells lacking one of the receptors lack normal IFN signaling (4, 5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5-13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15). Receptor dimerization drives the activation of cytosolic associated Janus family kina...

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“…The presence and number of TMs were predicted using the online software TOPCONS (http://topcons.cbr.su.se) [ 42 ]. Molecular weight and the isoelectric point of the deduced polypeptides were calculated using ExPasy (http://web.expasy.org/compute_pi).…”

Section: Tms Chromosomal Locations and Gene Duplication Analysis Ofmentioning

confidence: 99%

Genome-wide Identiﬁcation, Classiﬁcation and Expression Analysis of the Mildew Resistance Locus O ( MLO ) Gene Family in Sweet Orange ( Citrus sinensis )

Liu

JinWang

et al. 2017

Braz. arch. biol. technol.

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The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides

Cited by 838 publications

References 45 publications

Crystal Structure of the Substrate-Binding Domain from Listeria monocytogenes Bile-Resistance Determinant BilE

Crystal Structure of the Substrate-Binding Domain from Listeria monocytogenes Bile-Resistance Determinant BilE

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Genome-wide Identiﬁcation, Classiﬁcation and Expression Analysis of the Mildew Resistance Locus O ( MLO ) Gene Family in Sweet Orange ( Citrus sinensis )

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