Discovery of novel membrane binding structures and functions
- Kufareva, Irina Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
- Lenoir, Marc School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- Dancea, Felician School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- Sridhar, Pooja School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- Raush, Eugene Molsoft L.L.C., 11199 Sorrento Valley Road, S209, San Diego, CA 92121, USA.
- Bissig, Christin Biochemistry Department, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
- Gruenberg, Jean Biochemistry Department, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
- Abagyan, Ruben Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
- Overduin, Michael School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Published in:
- Biochemistry and Cell Biology. - Canadian Science Publishing. - 2014, vol. 92, no. 6, p. 555-563
English
The function of a protein is determined by its intrinsic activity in the context of its subcellular distribution. Membranes localize proteins within cellular compartments and govern their specific activities. Discovering such membrane-protein interactions is important for understanding biological mechanisms and could uncover novel sites for therapeutic intervention. We present a method for detecting membrane interactive proteins and their exposed residues that insert into lipid bilayers. Although the development process involved analysis of how C1b, C2, ENTH, FYVE, Gla, pleckstrin homology (PH), and PX domains bind membranes, the resulting membrane optimal docking area (MODA) method yields predictions for a given protein of known three-dimensional structures without referring to canonical membrane-targeting modules. This approach was tested on the Arf1 GTPase, ATF2 acetyltransferase, von Willebrand factor A3 domain, and Neisseria gonorrhoeae MsrB protein and further refined with membrane interactive and non-interactive FAPP1 and PKD1 pleckstrin homology domains, respectively. Furthermore we demonstrate how this tool can be used to discover unprecedented membrane binding functions as illustrated by the Bro1 domain of Alix, which was revealed to recognize lysobisphosphatidic acid (LBPA). Validation of novel membrane-protein interactions relies on other techniques such as nuclear magnetic resonance spectroscopy (NMR), which was used here to map the sites of micelle interaction. Together this indicates that genome-wide identification of known and novel membrane interactive proteins and sites is now feasible and provides a new tool for functional annotation of the proteome.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1139/bcb-2014-0074
- ISSN 0829-8211
- Persistent URL
- https://sonar.ch/global/documents/252823
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