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Molecular code for protein insertion in the endoplasmic reticulum membrane is similar for N-in-C-out and N-out-C-in transmembrane helices
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.
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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 41, 15702-15707 p.Article in journal (Refereed) Published
Abstract [en]

Transmembrane alpha-helices in integral membrane proteins can have two orientations in the membrane: N(in)-C(out) or N(out)-C(in). Previous studies of model N(out)-C(in) transmembrane segment have led to a detailed, quantitative picture of the "molecular code" that relates amino acid sequence to membrane insertion efficiency in vivo [Hessa T, et al. (2007) Molecular code for transmembrane helix recognition by the Sec61 translocon. Nature 450:1026-1030], but whether the same code applies also to N(in)-C(out) transmembrane helices is unknown. Here, we show that the contributions of individual amino acids to the overall efficiency of membrane insertion are similar for the two kinds of helices and that the threshold hydrophobicity for membrane insertion can be up to approximately 1 kcal/mol lower for N(in)-C(out) compared with N(out)-C(in) transmembrane helices, depending on the neighboring helices.

Place, publisher, year, edition, pages
2008. Vol. 105, no 41, 15702-15707 p.
Keyword [en]
membrane protein, positive-inside rule, Saccharomyces cerevisiae, topology, translocon
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-14917DOI: 10.1073/pnas.0804842105ISI: 000260240900014PubMedID: 18840693OAI: oai:DiVA.org:su-14917DiVA: diva2:181437
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Integration and topology of membrane proteins
Open this publication in new window or tab >>Integration and topology of membrane proteins
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane proteins comprise around 20-30% of most proteomes. They play important roles in most biochemical pathways. All receptors and ion channels are membrane proteins, which make them attractive targets for drug design. Membrane proteins insert and fold co-translationally into the endoplasmic reticular membrane of eukaryotic cells. The protein-conducting channel that inserts the protein into the membrane is called Sec61 translocon, which is a hetero-oligomeric channel that allows transmembrane segments to insert laterally into the lipid bilayer. The focus of this thesis is how the translocon recognizes the transmembrane helices and integrates them into the membrane.

We have investigated the sequence requirements for the translocon-mediated integration of a transmembrane α-helix into the ER by challenging the Sec61 translocon with designed polypeptide segments in an in vitro expression system that allows a quantitative assessment of membrane insertion efficiency. Our studies suggest that helices might interact with each other already during the membrane-insertion step, possibly forming helical hairpins that partition into the membrane as a single unit. Further, the insertion efficiency for Nin-Cout vs. Nout-Cin transmembrane helices and the integration efficiency of Alzheimer’s Aβ-peptide fragments has been investigated.

Finally, detailed topology mapping was performed on two biologically interesting proteins with unknown topology, the human seipin protein and Drosophila melanogaster odorant receptor OR83b.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik, 2009. 53 p.
Keyword
insertion, Sec61, translocation
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-8575 (URN)978-91-7155-827-5 (ISBN)
Public defence
2009-04-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
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Available from: 2009-03-12 Created: 2009-02-20 Last updated: 2016-02-23Bibliographically approved

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