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Repositioning of transmembrane alpha-helices during membrane protein folding
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Elofsson)
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Cristobal)
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2010 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 397, no 1, 190-201 p.Article in journal (Refereed) Published
Abstract [en]

We have determined the optimal placement of individual transmembrane helices in the Pyrococcus horikoshii Glt(Ph) glutamate transporter homolog in the membrane. The results are in close agreement with theoretical predictions based on hydrophobicity, but do not, in general, match the known three-dimensional structure, suggesting that transmembrane helices can be repositioned relative to the membrane during folding and oligomerization. Theoretical analysis of a database of membrane protein structures provides additional support for this idea. These observations raise new challenges for the structure prediction of membrane proteins and suggest that the classical two-stage model often used to describe membrane protein folding needs to be modified.

Place, publisher, year, edition, pages
2010. Vol. 397, no 1, 190-201 p.
Keyword [en]
membrane protein; GltPh; protein folding; membrane insertion
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-42790DOI: 10.1016/j.jmb.2010.01.042ISI: 000275785600013PubMedID: 20109468OAI: oai:DiVA.org:su-42790DiVA: diva2:351449
Available from: 2010-09-16 Created: 2010-09-14 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Intra- and intermolecular interactions in proteins: Studies of marginally hydrophobic transmembrane alpha-helices and protein-protein interactions.
Open this publication in new window or tab >>Intra- and intermolecular interactions in proteins: Studies of marginally hydrophobic transmembrane alpha-helices and protein-protein interactions.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Most of the processes in a living cell are carried out by proteins. Depending on the needs of the cell, different proteins will interact and form the molecular machines demanded for the moment. A subset of proteins called integral membrane proteins are responsible for the interchange of matter and information across the biological membrane, the lipid bilayer enveloping and defining the cell. Most of these proteins are co-translationally integrated into the membrane by the Sec translocation machinery.

This thesis addresses two questions that have emerged during the last decade. The first concerns membrane proteins: a number of α-helices have been observed to span the membrane in the obtained three-dimensional structures even though these helices are predicted not to be hydrophobic enough to be recognized by the translocon for integration. We show for a number of these marginally hydrophobic protein segments that they indeed do not insert well outside of their native context, but that their local sequence context can improve the level of integration mediated by the translocon. We also find that many of these helices are overlapped by more hydrophobic segments. We propose, supported by experimental results, that the latter are initially integrated into the membrane, followed by post-translational structural rearrangements. Finally, we investigate whether the integration of the marginally hydrophobic TMHs of the lactose permease of Escherichia coli is facilitated by the formation of hairpin structures. However our combined efforts of computational simulations and experimental investigations find no evidence for this.

The second question addressed in this thesis is that of the interpretation of the large datasets on which proteins that interact with each other in a cell. We have analyzed the results from several large-scale investigations concerning protein interactions in yeast and draw conclusions regarding the biases, strengths and weaknesses of these datasets and the methods used to obtain them.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholms universitet, 2010. 74 p.
Keyword
membrane proteins, membrane insertion, marginally hydrophobic helix, hydrophobicity, protein-protein interactions, LacY, GltPh
National Category
Biochemistry and Molecular Biology Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-42856 (URN)978-91-7447-111-3 (ISBN)
Public defence
2010-10-15, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense the following publications were not published and had a status as follows: Paper 2: In press; Paper 4 Manuscript.Available from: 2010-09-23 Created: 2010-09-16 Last updated: 2014-11-10Bibliographically approved

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Hedin, Linnea ECristobal, SusanaElofsson, Arnevon Heijne, Gunnar
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