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Topology Prediction of Membrane Proteins: Why, How and When?
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane proteins are of broad interest since they constitute a large fraction of the proteome in all organisms, up to 20-30%. They play a crucial role in many cellular processes mediating information flow and molecular transport across otherwise nearly impermeable membranes. Traditional three-dimensional structural analyses of membrane proteins are difficult to perform, which makes studies of other structural aspects important. The topology of an α-helical membrane protein is a two-dimensional description of how the protein is embedded in the membrane and gives valuable information on both structure and function.

This thesis is focused on predicting the topology of α-helical membrane proteins and on assessing and improving the prediction accuracy. Reliability scores have been derived for a number of prediction methods, and have been integrated into the widely used TMHMM predictor. The reliability score makes it possible to estimate the trustworthiness of a prediction.

Mapping the full topology of a membrane protein experimentally is time-consuming and cannot be done on a genome-wide scale. However, determination of the location of one part of a membrane protein relative to the membrane is feasible. We have analyzed the impact of incorporating such experimental information a priori into TMHMM predictions and show that the accuracy increases significantly. We further show that the C-terminal location of a membrane protein (inside or outside) is the optimal information to use as a constraint in the predictions.

By combining experimental techniques for determining the C-terminal location of membrane proteins with topology predictions, we have produced reliable topology models for the majority of all membrane proteins in the model organisms E. coli and S. cerevisiae. The results were further expanded to ~15,000 homologous proteins in 38 fully sequenced eukaryotic genomes. This large set of reliable topology models should be useful, in particular as the structural data for eukaryotic membrane proteins is very limited.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2007. , 61 p.
Keyword [en]
membrane protein, topology prediction, bioinformatics
National Category
Theoretical Chemistry
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-6875ISBN: 91-7155-397-5 (print)OAI: oai:DiVA.org:su-6875DiVA: diva2:197244
Public defence
2007-06-15, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2007-05-24 Created: 2007-05-15Bibliographically approved
List of papers
1. Reliability measures for membrane protein topology prediction algorithms
Open this publication in new window or tab >>Reliability measures for membrane protein topology prediction algorithms
2003 In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 327, no 3, 735-744 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24325 (URN)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15Bibliographically approved
2. Topology models for 37 Saccharomyces cerevisiae membrane proteins based on C-terminal reporter fusions and predictions
Open this publication in new window or tab >>Topology models for 37 Saccharomyces cerevisiae membrane proteins based on C-terminal reporter fusions and predictions
2003 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 278, no 12, 10208-10213 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24326 (URN)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15Bibliographically approved
3. Experimentally based topology models for E. coli inner membrane proteins
Open this publication in new window or tab >>Experimentally based topology models for E. coli inner membrane proteins
Show others...
2004 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 13, no 4, 937-945 p.Article in journal (Refereed) Published
Abstract [en]

Membrane protein topology predictions can be markedly improved by the inclusion of even very limited experimental information. We have recently introduced an approach for the production of reliable topology models based on a combination of experimental determination of the location (cytoplasmic or periplasmic) of a protein's C terminus and topology prediction. Here, we show that determination of the location of a protein's C terminus, rather than some internal loop, is the best strategy for large-scale topology mapping studies. We further report experimentally based topology models for 31 Escherichia coli inner membrane proteins, using methodology suitable for genome-scale studies.

Keyword
membrane proteins, topology, prediction, bioinformatics, fusion protein, PhoA, green fluorescent, protein, FP
Identifiers
urn:nbn:se:su:diva-24327 (URN)10.1110/ps.03553804 (DOI)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15 Last updated: 2017-12-13Bibliographically approved
4. Global topology analysis of the Escherichia coli inner membrane proteome
Open this publication in new window or tab >>Global topology analysis of the Escherichia coli inner membrane proteome
Show others...
2005 In: Science, ISSN 0036-8075, Vol. 308, no 5726, 1321-1323 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24328 (URN)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15Bibliographically approved
5. A global topology map of the Saccharomyces cerevisiae membrane proteome
Open this publication in new window or tab >>A global topology map of the Saccharomyces cerevisiae membrane proteome
2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 30, 11142-11147 p.Article in journal (Refereed) Published
Abstract [en]

The yeast Saccharomyces cerevisiae is, arguably, the best understood eukaryotic model organism, yet comparatively little is known about its membrane proteome. Here, we report the cloning and expression of 617 S. cerevisiae membrane proteins as fusions to a C-terminal topology reporter and present experimentally constrained topology models for 546 proteins. By homology, the experimental topology information can be extended to ≈15,000 membrane proteins from 38 fully sequenced eukaryotic genomes.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-24329 (URN)10.1073/pnas.0604075103 (DOI)
Note
Part of urn:nbn:se:su:diva-6875Available from: 2007-05-24 Created: 2007-05-15 Last updated: 2017-12-13Bibliographically approved

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