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Integration of Transmembrane Helices into the Endoplasmic Reticulum
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane proteins reside in cell and organelle membranes. They play significant roles in many processes vital to living cells. Receptors and ion channels are examples of membrane proteins that regulate the physiological state of the cell and are attractive targets for drug development.

In eukaryotic cells most membrane proteins insert and fold cotranslationally into the endoplasmic reticular membrane. The insertion process is mediated by the Sec61 translocon which is a hetero-oligomeric protein-conducting channel that allows transmembrane segments to exit laterally into the lipid bilayer. How the translocon recognizes the molecular characteristics of transmembrane helices and integrate them into the lipid bilayer is the focus of this thesis.

We have determined the sequence requirements for translocon-mediated integration of a transmembrane -helix into the ER membrane by challenging the Sec61 translocon with designed polypeptide segments in an in vitro expression system that permits quantitative assessment of membrane insertion efficiency. A biological hydrophobicity scale and a position-dependent free energy matrix have been developed, describing the contribution of each of the 20 amino acids in each position of a 19-residues long polypeptide segment to the overall free energy of a single transmembrane segment insertion. These studies suggest that the translocon provides direct contact between the nascent chain and the lipids in the membrane and that this protein-lipid interaction is the basis for the recognition of transmembrane helices in the translocon.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2006. , 100 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-1229ISBN: 91-1234-12-4 OAI: oai:DiVA.org:su-1229DiVA: diva2:189644
Public defence
2006-09-20, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00
Opponent
Supervisors
Available from: 2006-08-30 Created: 2006-08-30Bibliographically approved
List of papers
1. Stop-transfer efficiency of marginally hydrophobic segments depends on the length of the carboxy terminal tail
Open this publication in new window or tab >>Stop-transfer efficiency of marginally hydrophobic segments depends on the length of the carboxy terminal tail
2003 In: EMBO reports, ISSN 1469-221X, Vol. 4, no 2, 178-183 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22859 (URN)
Note
Part of urn:nbn:se:su:diva-1229Available from: 2006-08-30 Created: 2006-08-30Bibliographically approved
2. Recognition of transmembrane helices by the endoplasmic reticulum translocon
Open this publication in new window or tab >>Recognition of transmembrane helices by the endoplasmic reticulum translocon
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2005 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 433, no 7024, 377-381 p.Article in journal (Refereed) Published
Abstract [en]

Membrane proteins depend on complex translocation machineries for insertion into target membranes. Although it has long been known that an abundance of nonpolar residues in transmembrane helices is the principal criterion for membrane insertion, the specific sequence-coding for transmembrane helices has not been identified. By challenging the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments, we have determined the basic features of this code, including a 'biological' hydrophobicity scale. We find that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Our results indicate that direct protein - lipid interactions are critical during translocon-mediated membrane insertion.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-22860 (URN)10.1038/nature03216 (DOI)000226546200033 ()
Available from: 2006-08-30 Created: 2006-08-30 Last updated: 2017-12-13Bibliographically approved
3. Membrane insertion of a potassium channel voltage sensor
Open this publication in new window or tab >>Membrane insertion of a potassium channel voltage sensor
2005 In: Science, Vol. 307, no 5714, 1427- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22861 (URN)
Note
Part of urn:nbn:se:su:diva-1229Available from: 2006-08-30 Created: 2006-08-30Bibliographically approved
4. A quantitative analysis of translocon-mediated insertion of transmembrane alpha-helices
Open this publication in new window or tab >>A quantitative analysis of translocon-mediated insertion of transmembrane alpha-helices
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(English)Manuscript (Other academic)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-22862 (URN)
Available from: 2006-08-30 Created: 2006-08-30 Last updated: 2016-02-23Bibliographically approved

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