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Molecular recognition of a single sphingolipid species by a protein's transmembrane domain
Heidelberg University.
Heidelberg University.
Heidelberg University.
Stockholm University.
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, 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.
Keyword [en]
TO-GOLGI TRANSPORT, ENDOPLASMIC-RETICULUM, LIVING CELLS, GXXXG MOTIF, SPHINGOMYELIN, COPI, MEMBRANES, VESICLES, ASSOCIATION, CHOLESTEROL
National Category
Biophysics Bioinformatics and Systems Biology Theoretical Chemistry
Research subject
SRA - E-Science (SeRC)
Identifiers
URN: urn:nbn:se:kth:diva-82583DOI: 10.1038/nature10742ISI: 000299471800044PubMedID: 22230960Scopus ID: 2-s2.0-84856213807OAI: oai:DiVA.org:kth-82583DiVA: diva2:498398
Funder
EU, European Research Council, 209825EU, European Research Council, AdG232648Swedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20120403

Available from: 2012-02-12 Created: 2012-02-12 Last updated: 2017-12-07Bibliographically approved

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Lindahl, Erik

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