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Sequence-based predictions of membrane-protein topology, homology and insertion
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane proteins comprise around 20-30% of a typical proteome and play crucial roles in a wide variety of biochemical pathways. Apart from their general biological significance, membrane proteins are of particular interest to the pharmaceutical industry, being targets for more than half of all available drugs. This thesis focuses on prediction methods for membrane proteins that ultimately rely on their amino acid sequence only.

By identifying soluble protein domains in membrane protein sequences, we were able to constrain and improve prediction of membrane protein topology, i.e. what parts of the sequence span the membrane and what parts are located on the cytoplasmic and extra-cytoplasmic sides. Using predicted topology as input to a profile-profile based alignment protocol, we managed to increase sensitivity to detect distant membrane protein homologs.

Finally, experimental measurements of the level of membrane integration of systematically designed transmembrane helices in vitro were used to derive a scale of position-specific contributions to helix insertion efficiency for all 20 naturally occurring amino acids. Notably, position within the helix was found to be an important factor for the contribution to helix insertion efficiency for polar and charged amino acids, reflecting the highly anisotropic environment of the membrane. Using the scale to predict natural transmembrane helices in protein sequences revealed that, whereas helices in single-spanning proteins are typically hydrophobic enough to insert by themselves, a large part of the helices in multi-spanning proteins seem to require stabilizing helix-helix interactions for proper membrane integration. Implementing the scale to predict full transmembrane topologies yielded results comparable to the best statistics-based topology prediction methods.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 57 p.
Keyword [en]
membrane protein, topology prediction, hidden markov model, homology detection, Sec translocon
National Category
Bioinformatics (Computational Biology)
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-8126ISBN: 978-91-628-7565-7 (print)OAI: oai:DiVA.org:su-8126DiVA: diva2:199611
Public defence
2008-09-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00 (English)
Opponent
Supervisors
Available from: 2008-08-28 Created: 2008-08-28 Last updated: 2009-05-12Bibliographically approved
List of papers
1. Improved membrane protein topology prediction by domain assignments
Open this publication in new window or tab >>Improved membrane protein topology prediction by domain assignments
2005 In: Protein Science, ISSN 0961-8368, Vol. 14, no 7, 1723-1728 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25365 (URN)
Note
Part of urn:nbn:se:su:diva-8126Available from: 2008-08-28 Created: 2008-08-28Bibliographically approved
2. Remote homology detection of integral membrane proteins using conserved sequence features
Open this publication in new window or tab >>Remote homology detection of integral membrane proteins using conserved sequence features
2008 (English)In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 71, no 3, 1387-1399 p.Article in journal (Refereed) Published
Keyword
Conserved Sequence, Databases; Protein, Hydrophobicity, Markov Chains, Membrane Proteins/*chemistry, Sensitivity and Specificity, Sequence Alignment/*methods, Sequence Analysis; Protein/methods, Sequence Homology; Amino Acid
Identifiers
urn:nbn:se:su:diva-14855 (URN)10.1002/prot.21825 (DOI)000255269200028 ()18076048 (PubMedID)
Available from: 2008-11-20 Created: 2008-11-20 Last updated: 2017-12-13Bibliographically approved
3. Molecular code for transmembrane-helix recognition by the Sec61 translocon
Open this publication in new window or tab >>Molecular code for transmembrane-helix recognition by the Sec61 translocon
Show others...
2007 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, no 7172, 1026-1030 p.Article in journal (Refereed) Published
Abstract [en]

Transmembrane alpha-helices in integral membrane proteins are recognized co-translationally and inserted into the membrane of the endoplasmic reticulum by the Sec61 translocon. A full quantitative description of this phenomenon, linking amino acid sequence to membrane insertion efficiency, is still lacking. Here, using in vitro translation of a model protein in the presence of dog pancreas rough microsomes to analyse a large number of systematically designed hydrophobic segments, we present a quantitative analysis of the position- dependent contribution of all 20 amino acids to membrane insertion efficiency, as well as of the effects of transmembrane segment length and flanking amino acids. The emerging picture of translocon- mediated transmembrane helix assembly is simple, with the critical sequence characteristics mirroring the physical properties of the lipid bilayer.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-25367 (URN)10.1038/nature06387 (DOI)000251579900075 ()
Available from: 2008-08-28 Created: 2008-08-28 Last updated: 2017-12-13Bibliographically approved
4. Prediction of membrane-protein topology from first principles
Open this publication in new window or tab >>Prediction of membrane-protein topology from first principles
Show others...
2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 20, 7177-7181 p.Article in journal (Refereed) Published
Keyword
Animals, Biophysics/*methods, Cell Membrane/*metabolism, Chemistry; Physical/methods, Databases; Protein, Lipids/chemistry, Membrane Proteins/*chemistry, Models; Statistical, Probability, Protein Binding, Protein Conformation, Protein Structure; Secondary, Proteomics/methods, Sequence Analysis; Protein, Thermodynamics
Identifiers
urn:nbn:se:su:diva-14850 (URN)10.1073/pnas.0711151105 (DOI)000256162900015 ()18477697 (PubMedID)
Available from: 2008-11-20 Created: 2008-11-20 Last updated: 2017-12-13Bibliographically approved

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