Sequence-based predictions of membrane-protein topology, homology and insertion
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Membrane proteins comprise around 20-30% of a typical proteome and play crucial roles in a wide variety of biochemical pathways. Apart from their general biological significance, membrane proteins are of particular interest to the pharmaceutical industry, being targets for more than half of all available drugs. This thesis focuses on prediction methods for membrane proteins that ultimately rely on their amino acid sequence only.
By identifying soluble protein domains in membrane protein sequences, we were able to constrain and improve prediction of membrane protein topology, i.e. what parts of the sequence span the membrane and what parts are located on the cytoplasmic and extra-cytoplasmic sides. Using predicted topology as input to a profile-profile based alignment protocol, we managed to increase sensitivity to detect distant membrane protein homologs.
Finally, experimental measurements of the level of membrane integration of systematically designed transmembrane helices in vitro were used to derive a scale of position-specific contributions to helix insertion efficiency for all 20 naturally occurring amino acids. Notably, position within the helix was found to be an important factor for the contribution to helix insertion efficiency for polar and charged amino acids, reflecting the highly anisotropic environment of the membrane. Using the scale to predict natural transmembrane helices in protein sequences revealed that, whereas helices in single-spanning proteins are typically hydrophobic enough to insert by themselves, a large part of the helices in multi-spanning proteins seem to require stabilizing helix-helix interactions for proper membrane integration. Implementing the scale to predict full transmembrane topologies yielded results comparable to the best statistics-based topology prediction methods.
Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 57 p.
membrane protein, topology prediction, hidden markov model, homology detection, Sec translocon
Bioinformatics (Computational Biology)
Research subject Biochemistry
IdentifiersURN: urn:nbn:se:su:diva-8126ISBN: 978-91-628-7565-7OAI: oai:DiVA.org:su-8126DiVA: diva2:199611
2008-09-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00 (English)
Helms, Volkhard, Prof.
von Heijne, Gunnar, Prof.
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