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- Bernsel, Andreas, 1978-
(författare)
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Sequence-based predictions of membrane-protein topology, homology and insertion
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Metzger, Jennifer, et al.
(författare)
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Predicting Structural and Functional Properties of Membrane Proteins from Protein Sequence
- 2011
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Ingår i: Annual Reports in Computational Chemistry. - Amsterdam : Elsevier Science BV. - 9780444543028 ; , s. 39-64
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Bokkapitel (refereegranskat)abstract
- Integral transmembrane (TM) proteins are essential constituents of biological membranes where they fulfill a variety of important cellular functions. Because of difficulties with determining their structures by experimental techniques, comparably few 3D structures of membrane proteins are known so far. Therefore, computational methods trained on the available structures using only the protein sequence as input have become important tools in this field. In this chapter, we give a short introduction to the topic and then summarize recent bioinformatics tools for the prediction of structural as well as functional properties of alpha-helical and beta-barrel TM proteins. We present methods that allow predicting the locations of alpha-helical and beta-strand TM segments, to determine the exposure status of residues in the TM region to the surrounding lipids, and that allow functional annotations from the protein sequence.
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