| 1. |
- Bernsel, Andreas, et al.
(författare)
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TOPCONS : consensus prediction of membrane protein topology
- 2009
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 37:Suppl. 2, s. W465-W468
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Tidskriftsartikel (refereegranskat)abstract
- TOPCONS (http://topcons.net/) is a web server for consensus prediction of membrane protein topology. The underlying algorithm combines an arbitrary number of topology predictions into one consensus prediction and quantifies the reliability of the prediction based on the level of agreement between the underlying methods, both on the protein level and on the level of individual TM regions. Benchmarking the method shows that overall performance levels match the best available topology prediction methods, and for sequences with high reliability scores, performance is increased by approximately 10 percentage points. The web interface allows for constraining parts of the sequence to a known inside/outside location, and detailed results are displayed both graphically and in text format.
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| 2. |
- Hedin, Linnea E., et al.
(författare)
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Membrane Insertion of Marginally Hydrophobic Transmembrane Helices Depends on Sequence Context
- 2010
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 396:1, s. 221-229
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Tidskriftsartikel (refereegranskat)abstract
- In mammalian cells, most integral membrane proteins are initially inserted into the endoplasmic reticulum membrane by the so-called Sec61 translocon. However, recent predictions suggest that many transmembrane helices (TMHs) in multispanning membrane proteins are not sufficiently hydrophobic to be recognized as such by the translocon. In this study, we have screened 16 marginally hydrophobic TMHs from membrane proteins of known three-dimensional structure. Indeed, most of these TMHs do not insert efficiently into the endoplasmic reticulum membrane by themselves. To test if loops or TMHs immediately upstream or downstream of a marginally hydrophobic helix might influence the insertion efficiency, insertion of marginally hydrophobic helices was also studied in the presence of their neighboring loops and helices. The results show that flanking loops and nearest-neighbor TMHs are sufficient to ensure the insertion of many marginally hydrophobic helices. However, for at least two of the marginally hydrophobic helices, the local interactions are not enough, indicating that post-insertional rearrangements are involved in the folding of these proteins.
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| 3. |
- Hennerdal, Aron, 1981-, et al.
(författare)
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A guideline to α-helical membrane protein topology prediction
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- All living organisms have a “membrane proteome” that mainly consists of α-helical mem- brane proteins containing one or more TM-helices. Prediction methods have been extensively used to identify as well as to classify the topology of these proteins. For current state-of-the- art methods, the prediction of correct topology of membrane proteins has been reported to be above 80%. However, this performance has only been observed in small and possibly biased datasets. Here, we add four “genome-scale” datasets, including a recent large set of experimen- tally validated membrane proteins with glycosylation sites. This set is also used to examine whether the qualities of topology predictions hold and if any prediction methods perform con- sistently better than others. We find that methods utilizing multiple sequence alignments are overall superior to methods that do not. The best performance is obtained by TOPCONS, a consensus method which combines several of the other prediction methods. Further, we show that the accuracy is most likely lower in eukaryotes than for prokaryotic proteins as the agree- ment between the predictors is significantly lower there. Finally, we show that three related methods, Phobius, Phillius and PolyPhobius, that incorporate a specific signal peptide module are superior to all other methods at the task of distinguishing between membrane and non- membrane proteins.
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| 4. |
- Hennerdal, Aron, 1981-
(författare)
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Application of membrane protein topology prediction
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Membrane proteins often have essential functions in the cell and many are important drug targets, yet only a small fraction of available protein structures are of membrane proteins. Experimental techniques for elucidating membrane protein structures have proven laborious and expensive, opening the field for comparatively inexpensive computational modeling. Topology prediction addresses a sub-problem of structure prediction for α-helical membrane proteins by modeling which parts of the peptide chain are in, and which parts are on either side, of the membrane. This work describes an algorithm for combining the results of several topology prediction methods to increase prediction accuracy and to quantify prediction reliability, and a faster implementation of the algorithm applicable to large-scale genome data. Further, topology prediction is applied, together with other sequence-based methods, to detect duplications in membrane proteins in whole genomes. We find more duplications in the genomes of yeast and E. coli than in human, possibly due to the abundance of nonduplicated GPCRs in human. A gene duplication and subsequent fusion event constitute a likely origin for duplicated proteins, yet only for one superfamily, the AcrB Multidrug Efflux Pump, do we find the duplicated unit in its nonduplicated form. This apparent scarcity of nonduplicated forms is confirmed when extending the study to the whole human genome. Finally, a benchmark study of topology prediction on several comparably large datasets is described. We confirm previous results showing that methods utilizing homology information top the ranking of topology prediction methods. We also see that the separation of membrane proteins from non-membrane proteins has a partially different set of requirements than topology prediction of membrane proteins, and we suggest a pipeline using different methods for these two tasks.
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| 5. |
- Hennerdal, Aron, et al.
(författare)
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Internal duplications in alpha-helical membrane protein topologies are common but the nonduplicated forms are rare
- 2010
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Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2305-2318
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Tidskriftsartikel (refereegranskat)abstract
- Many alpha-helical membrane proteins contain internal symmetries, indicating that they might have evolved through a gene duplication and fusion event Here, we have characterized internal duplications among membrane proteins of known structure and in three complete genomes We found that the majority of large transmembrane (TM) proteins contain an internal duplication The duplications found showed a large variability both in the number of TM-segments included and in their orientation Surprisingly, an approximately equal number of antiparallel duplications and parallel duplications were found However, of all 11 superfamilies with an internal duplication, only for one, the AcrB Multidrug Efflux Pump, the duplicated unit could be found in its nonduplicated form An evolutionary analysis of the AcrB homologs indicates that several independent fusions have occurred, including the fusion of the SecD and SecF proteins into the 12-TM-protein SecDF in Brucella and Staphylococcus aureus In one additional case, the Vitamin B-12 transporter-like ABC transporters, the protein had undergone an additional fusion to form protein with 20 TM-helices in several bacterial genomes Finally, homologs to all human membrane proteins were used to detect the presence of duplicated and nonduplicated proteins This confirmed that only in rare cases can homologs with different duplication status be found, although internal symmetry is frequent among these proteins One possible explanation is that it is frequent that duplication and fusion events happen simultaneously and that there is almost always a strong selective advantage for the fused form
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| 6. |
- Hennerdal, Aron, 1981-, et al.
(författare)
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Rapid membrane protein topology prediction
- 2011
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 27:9, s. 1322-1323
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Tidskriftsartikel (refereegranskat)abstract
- State-of-the-art methods for topology of α-helical membrane proteins are based on the use of time-consuming multiple sequence alignments obtained from PSI-BLAST or other sources. Here, we examine if it is possible to use the consensus of topology prediction methods that are based on single sequences to obtain a similar accuracy as the more accurate multiple sequence-based methods. Here, we show that TOPCONS-single performs better than any of the other topology prediction methods tested here, but ~6% worse than the best method that is utilizing multiple sequence alignments. AVAILABILITY AND IMPLEMENTATION: TOPCONS-single is available as a web server from http://single.topcons.net/ and is also included for local installation from the web site. In addition, consensus-based topology predictions for the entire international protein index (IPI) is available from the web server and will be updated at regular intervals.
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| 7. |
- Tsirigos, Konstantinos D., et al.
(författare)
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A guideline to proteome-wide alpha-helical membrane protein topology predictions
- 2013
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Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 12:14, s. 2282-2294
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Tidskriftsartikel (refereegranskat)abstract
- For current state-of-the-art methods, the prediction of correct topology of membrane proteins has been reported to be above 80%. However, this performance has only been observed in small and possibly biased data sets obtained from protein structures or biochemical assays. Here, we test a number of topology predictors on an unseen set of proteins of known structure and also on four genome-scale data sets, including one recent large set of experimentally validated human membrane proteins with glycosylated sites. The set of glycosylated proteins is also used to examine the ability of prediction methods to separate membrane from nonmembrane proteins. The results show that methods utilizing multiple sequence alignments are overall superior to methods that do not. The best performance is obtained by TOPCONS, a consensus method that combines several of the other prediction methods. The best methods to distinguish membrane from nonmembrane proteins belong to the Phobius group of predictors. We further observe that the reported high accuracies in the smaller benchmark sets are not quite maintained in larger scale benchmarks. Instead, we estimate the performance of the best prediction methods for eukaryotic membrane proteins to be between 60% and 70%. The low agreement between predictions from different methods questions earlier estimates about the global properties of the membrane proteome. Finally, we suggest a pipeline to estimate these properties using a combination of the best predictors that could be applied in large-scale proteomics studies of membrane proteins.
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