title: Concentration Dependent Ion-Protein Interaction Patterns Underlying Protein Oligomerization Behaviours.
abstract: Salts and proteins comprise two of the basic molecular components of biological materials. Kosmotropic/chaotropic co-solvation and matching ion water affinities explain basic ionic effects on protein aggregation observed in simple solutions. However, it is unclear how these theories apply to proteins in complex biological environments and what the underlying ionic binding patterns are. Using the positive ion Ca(2+) and the negatively charged membrane protein SNAP25, we studied ion effects on protein oligomerization in solution, in native membranes and in molecular dynamics (MD) simulations. We find that concentration-dependent ion-induced protein oligomerization is a fundamental chemico-physical principle applying not only to soluble but also to membrane-anchored proteins in their native environment. Oligomerization is driven by the interaction of Ca(2+) ions with the carboxylate groups of aspartate and glutamate. From low up to middle concentrations, salt bridges between Ca(2+) ions and two or more protein residues lead to increasingly larger oligomers, while at high concentrations oligomers disperse due to overcharging effects. The insights provide a conceptual framework at the interface of physics, chemistry and biology to explain binding of ions to charged protein surfaces on an atomistic scale, as occurring during protein solubilisation, aggregation and oligomerization both in simple solutions and membrane systems.
authors.affiliation: Membrane Biochemistry, Life &Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Batoulis
authors.affiliation: Membrane Biochemistry, Life &Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Schmidt
authors.affiliation: Membrane Biochemistry, Life &Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Weber
authors.affiliation: Membrane Biochemistry, Life &Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Jan-Gero
authors.initials: JG
authors.lastname: Schloetel
authors.affiliation: Life Science Informatics B-IT, Computational Structural Biology, University of Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kandt
authors.affiliation: Membrane Biochemistry, Life &Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lang
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007477:Ions / Q000737:chemistry* / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D018613:Microscopy, Confocal; D056004:Molecular Dynamics Simulation; D016716:PC12 Cells; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D007477:Ions; D011506:Proteins; D050825:Synaptosomal-Associated Protein 25; D049452:Green Fluorescent Proteins; D008274:Magnesium; D002118:Calcium