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Large Tilts in Transmembrane Helices Can Be Induced during Tertiary Structure Formation
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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2014 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 426, no 13, 2529-2538 p.Article in journal (Refereed) Published
Abstract [en]

While early structural models of helix-bundle integral membrane proteins posited that the transmembrane a-helices [transmembrane helices (TMHs)] were orientated more or less perpendicular to the membrane plane, there is now ample evidence from high-resolution structures that many TMHs have significant tilt angles relative to the membrane. Here, we address the question whether the tilt is an intrinsic property of the TMH in question or if it is imparted on the TMH during folding of the protein. Using a glycosylation mapping technique, we show that four highly tilted helices found in multi-spanning membrane proteins all have much shorter membrane-embedded segments when inserted by themselves into the membrane than seen in the high-resolution structures. This suggests that tilting can be induced by tertiary packing interactions within the protein, subsequent to the initial membrane-insertion step.

Place, publisher, year, edition, pages
2014. Vol. 426, no 13, 2529-2538 p.
Keyword [en]
transnnembrane helix, membrane protein folding, translocon
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-106063DOI: 10.1016/j.jmb.2014.04.020ISI: 000337780200009OAI: oai:DiVA.org:su-106063DiVA: diva2:735757
Note

AuthorCount:9;

Available from: 2014-07-31 Created: 2014-07-21 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Marginally hydrophobic transmembrane α-helices shaping membrane protein folding
Open this publication in new window or tab >>Marginally hydrophobic transmembrane α-helices shaping membrane protein folding
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Most membrane proteins are inserted into the membrane co-translationally utilizing the translocon, which allows a sufficiently long and hydrophobic stretch of amino acids to partition into the membrane. However, X-ray structures of membrane proteins have revealed that some transmembrane helices (TMHs) are surprisingly hydrophilic. These marginally hydrophobic transmembrane helices (mTMH) are not recognized as TMHs by the translocon in the absence of local sequence context.

We have studied three native mTMHs, which were previously shown to depend on a subsequent TMH for membrane insertion. Their recognition was not due to specific interactions. Instead, the presence of basic amino acids in their cytoplasmic loop allowed membrane insertion of one of them. In the other two, basic residues are not sufficient unless followed by another, hydrophobic TMH. Post-insertional repositioning are another way to bring hydrophilic residues into the membrane. We show how four long TMHs with hydrophilic residues seen in X-ray structures, are initially inserted as much shorter membrane-embedded segments. Tilting is thus induced after membrane-insertion, probably through tertiary packing interactions within the protein.

Aquaporin 1 illustrates how a mTMH can shape membrane protein folding and how repositioning can be important in post-insertional folding. It initially adopts a four-helical intermediate, where mTMH2 and TMH4 are not inserted into the membrane. Consequently, TMH3 is inserted in an inverted orientation. The final conformation with six TMHs is formed by TMH2 and 4 entering the membrane and TMH3 rotating 180°. Based on experimental and computational results, we propose a mechanism for the initial step in the folding of AQP1: A shift of TMH3 out from membrane core allows the preceding regions to enter the membrane, which provides flexibility for TMH3 to re-insert in its correct orientation.

Place, publisher, year, edition, pages
Stockholm: Department of biochemistry and biophysics, Stockholm University, 2014. 66 p.
Keyword
membrane protein folding, hydrophobicity, translocon, transmembrane helix, marginally hydrophobic transmembrane helices, orientational preference, positive inside rule, aquaporin 1
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-109335 (URN)978-91-7649-050-1 (ISBN)
Public defence
2014-12-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 13:00 (English)
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Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2014-11-27 Created: 2014-11-18 Last updated: 2014-11-28Bibliographically approved

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Virkki, MinttuPeters, ChristophShu, NanjiangTsirigos, Konstantinos D.Elofsson, Arnevon Heijne, GunnarNilsson, IngMarie
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