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Analysis of transmembrane helix integration in the endoplasmic reticulum in S. cerevisiae
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Journal of molecular biology, ISSN 1089-8638, Vol. 386, no 5, 1222-8 p.Article in journal (Refereed) Published
Abstract [en]

What sequence features in integral membrane proteins determine which parts of the polypeptide chain will form transmembrane alpha-helices and which parts will be located outside the lipid bilayer? Previous studies on the integration of model transmembrane segments into the mammalian endoplasmic reticulum (ER) have provided a rather detailed quantitative picture of the relation between amino acid sequence and membrane-integration propensity for proteins targeted to the Sec61 translocon. We have now carried out a comparative study of the integration of N out-C in-orientated 19-residue-long polypeptide segments into the ER of the yeast Saccharomyces cerevisiae. We find that the 'threshold hydrophobicity' required for insertion into the ER membrane is very similar in S. cerevisiae and in mammalian cells. Further, when comparing the contributions to the apparent free energy of membrane insertion of the 20 natural amino acids between the S. cerevisiae and the mammalian ER, we find that the two scales are strongly correlated but that the absolute difference between the most hydrophobic and most hydrophilic residues is approximately 2-fold smaller in S. cerevisiae.

Place, publisher, year, edition, pages
2009. Vol. 386, no 5, 1222-8 p.
Keyword [en]
membrane protein, membrane insertion, endoplasmic reticulum, hydrophobicity, Saccharomyces cerevisiae
National Category
Natural Sciences
Research subject
Biophysics; Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-33928DOI: 10.1016/j.jmb.2009.01.027ISI: 000264383500004PubMedID: 19452628OAI: oai:DiVA.org:su-33928DiVA: diva2:283819
Available from: 2009-12-30 Created: 2009-12-30 Last updated: 2013-11-05Bibliographically approved
In thesis
1. Membrane Protein Biogenesis in Saccharomyces cerevisiae
Open this publication in new window or tab >>Membrane Protein Biogenesis in Saccharomyces cerevisiae
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membranes are hydrophobic barriers that define the outer boundaries and internal compartments of living cells. Membrane proteins are the gates in these barriers, and they perform vital functions in the highly regulated transport of matter and information across membranes. Membrane proteins destined for the endoplasmic reticulum are targeted either co- or post-translationally to the Sec61 translocon, the major translocation machinery in eukaryotic cells, which allows for lateral partitioning of hydrophobic segments into the lipid bilayer. This thesis aims to acquire insights into the mechanism of membrane protein insertion and the role of different translocon components in targeting, insertion and topogenesis, using the yeast Saccharomyces cerevisiae as a model organism.

By measuring the insertion efficiency of a set of model proteins, we studied the sequence requirements for Sec61-mediated insertion of an α-helical transmembrane segment and established a ‘biological hydrophobicity scale’ in yeast, which describes the individual contributions of the 20 amino acids to insertion. Systematic mutagenesis and photo-crosslinking of the Sec61 translocon revealed key residues in the lateral gate that modulate the threshold hydrophobicity for membrane insertion and transmembrane segment orientation. Further, my studies demonstrate that the translocon-associated Sec62 is important not only for post-translational targeting, but also for the insertion and topogenesis of moderately hydrophobic signal anchor proteins and the C-terminal translocation of multi-spanning membrane proteins. Finally, nuclearly encoded mitochondrial membrane proteins were found to evade mis-targeting to the endoplasmic reticulum by containing short C-terminal tails.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2013. 72 p.
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-95376 (URN)978-91-7447-798-6 (ISBN)
Public defence
2013-12-13, Nordenskiöld Lecture Hall, Geo-Science Building, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 4: Manuscript; Paper 5: Manuscript

Available from: 2013-11-21 Created: 2013-10-26 Last updated: 2014-07-25Bibliographically approved

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