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Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2012 (English)In: Nature, ISSN 0028-0836, Vol. 481, no 7382, 525-529 p.Article in journal (Refereed) Published
Abstract [en]

Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

Place, publisher, year, edition, pages
2012. Vol. 481, no 7382, 525-529 p.
National Category
Biochemistry and Molecular Biology
Research subject
URN: urn:nbn:se:su:diva-72360DOI: 10.1038/nature10742ISI: 000299471800044OAI: diva2:492867
EU, European Research Council, 232648Swedish Research Council, A0525002
Available from: 2012-02-10 Created: 2012-02-08 Last updated: 2014-11-10Bibliographically approved
In thesis
1. Protein Interactions from the Molecular to the Domain Level
Open this publication in new window or tab >>Protein Interactions from the Molecular to the Domain Level
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The basic unit of life is the cell, from single-cell bacteria to the largest creatures on the planet. All cells have DNA, which contains the blueprint for proteins. This information is transported in the form of messenger RNA from the genome to ribosomes where proteins are produced. Proteins are the main functional constituents of the cell, they usually have one or several functions and are the main actors in almost all essential biological processes. Proteins are what make the cell alive. Proteins are found as solitary units or as part of large complexes. Proteins can be found in all parts of the cell, the most common place being the cytoplasm, a central space in all cells. They are also commonly found integrated into or attached to various membranes.

Membranes define the cell architecture. Proteins integrated into the membrane have a wide number of responsibilities: they are the gatekeepers of the cell, they secrete cellular waste products, and many of them are receptors and enzymes.

The main focus of this thesis is the study of protein interactions, from the molecular level up to the protein domain level.

In paper I use reoccurring local protein structures to try and predict what sections of a protein interacts with another part using only sequence information. In papers II and III we use a randomization approach on a membrane protein motif that we know interacts with a sphingomyelin lipid to find other candidate proteins that interact with sphingolipids. These are then experimentally verified as sphingolipid-binding. In the last paper, paper IV, we look at how protein domain interaction networks overlap and can be evaluated.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2014. 52 p.
Protein interactions, protein domains, membrane proteins
National Category
Bioinformatics (Computational Biology)
Research subject
Biochemistry towards Bioinformatics
urn:nbn:se:su:diva-101795 (URN)978-91-7447-854-9 (ISBN)
Public defence
2014-04-25, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2014-04-03 Created: 2014-03-17 Last updated: 2014-07-07Bibliographically approved

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Björkholm, PatrikElofsson, Arnevon Heijne, Gunnar
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