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Protein-lipid interactions: correlation of a predictive algorithm for lipid-binding sites with three-dimensional structural data.

David L Scott·Gerold Diez·Wolfgang H Goldmann
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Abstract

BACKGROUND: Over the past decade our laboratory has focused on understanding how soluble cytoskeleton-associated proteins interact with membranes and other lipid aggregates. Many protein domains mediating specific cell membrane interactions appear by fluorescence microscopy and other precision techniques to be partially inserted into the lipid bilayer. It is unclear whether these protein-lipid-interactions are dependent on shared protein motifs or unique regional physiochemistry, or are due to more global characteristics of the protein. RESULTS: We have developed a novel computational program that predicts a protein's lipid-binding site(s) from primary sequence data. Hydrophobic labeling, Fourier transform infrared spectroscopy (FTIR), film balance, T-jump, CD spectroscopy and calorimetry experiments confirm that the interfaces predicted for several key cytoskeletal proteins (alpha-actinin, Arp2, CapZ, talin and vinculin) partially insert into lipid aggregates. The validity of these predictions is supported by an analysis of the available three-dimensional structural data. The lipid interfaces predicted by our algorithm generally contain energetically favorable secondary structures (e.g., an amphipathic alpha-helix flanked by a flexible hinge or loop region), are solvent-exposed in the intact protein, and possess favorable local or global electrostatic properties. CONCLUSION: At present, there are few reliable methods to determine the region of a protein that mediates biologically important interactions with lipids or lipid aggregates. Our matrix-based algorithm predicts lipid interaction sites that are consistent with the available biochemical and structural data. To determine whether these sites are indeed correctly identified, and whether use of the algorithm can be safely extended to other classes of proteins, will require further mapping of these sites, including genetic manipulation and/or targeted crystallography.

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AlgorithmsAmino Acid SequenceBinding SitesCytoskeletal ProteinsLipid MetabolismModels, BiologicalModels, MolecularProtein BindingProtein ConformationJournal ArticleResearch Support, Non-U.S. Gov't

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David L Scott, Gerold Diez, Wolfgang H Goldmann. 2006-03-28. Protein-lipid interactions: correlation of a predictive algorithm for lipid-binding sites with three-dimensional structural data.. https://doi.org/10.1186/1742-4682-3-17

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