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Defining the metal specificity of a multifunctional biofilm adhesion protein.

ABSTRACT: The accumulation associated protein (Aap) of Staphylococcus epidermidis mediates intercellular adhesion events necessary for biofilm growth. This process depends upon Zn2+ -induced self-assembly of G5 domains within the B-repeat region of the protein, forming anti-parallel, intertwined protein "ropes" between cells. Pleomorphism in the Zn2+ -coordinating residues was observed in previously solved crystal structures, suggesting that the metal binding site might accommodate other transition metals and thereby support dimerization. By use of carefully selected buffer systems and a specialized approach to analyze sedimentation velocity analytical ultracentrifugation data, we were able to analyze low-affinity metal binding events in solution. Our data show that both Zn2+ and Cu2+ support B-repeat assembly, whereas Mn2+ , Co2+ , and Ni2+ bind to Aap but do not support self-association. As the number of G5 domains are increased in longer B-repeat constructs, the total concentration of metal required for dimerization decreases and the transition between monomer and dimer becomes more abrupt. These characteristics allow Aap to function as an environmental sensor that regulates biofilm formation in response to local concentrations of Zn2+ and Cu2+ , both of which are implicated in immune cell activity.

SUBMITTER: Chaton CT

PROVIDER: S-EPMC5606542 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Defining the metal specificity of a multifunctional biofilm adhesion protein.

Chaton Catherine T CT Herr Andrew B AB

Protein science : a publication of the Protein Society 20170725 10

The accumulation associated protein (Aap) of Staphylococcus epidermidis mediates intercellular adhesion events necessary for biofilm growth. This process depends upon Zn<sup>2+</sup> -induced self-assembly of G5 domains within the B-repeat region of the protein, forming anti-parallel, intertwined protein "ropes" between cells. Pleomorphism in the Zn<sup>2+</sup> -coordinating residues was observed in previously solved crystal structures, suggesting that the metal binding site might accommodate o ...[more]

PMID: 28707417

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Project description:Protein-carbohydrate interactions are significant in a wide range of biological processes, disruption of which has been implicated in many different diseases. The capability of glycan-binding proteins (GBPs) to specifically bind to the corresponding glycans allows GBPs to be utilized in glycan biomarker detection or conversely to serve as targets for therapeutic intervention. However, understanding the structural origins of GBP specificity has proven to be challenging due to their typically low binding affinities (mM) and their potential to display broad or complex specificities. Here we perform molecular dynamics (MD) simulations and post-MD energy analyses with the Poisson-Boltzmann and generalized Born solvent models (MM-PB/GBSA) of the Erythrina cristagalli lectin (ECL) with its known ligands, and with new cocrystal structures reported herein. While each MM-PB/GBSA parametrization resulted in different estimates of the desolvation free energy, general trends emerged that permit us to define GBP binding preferences in terms of ligand substructure specificity. Additionally, we have further decomposed the theoretical interaction energies into contributions made between chemically relevant functional groups. Based on these contributions, the functional groups in each ligand can be assembled into a pharmacophore comprised of groups that are either critical for binding, or enhance binding, or are noninteracting. It is revealed that the pharmacophore for ECL consists of the galactopyranose (Gal) ring atoms along with C6 and the O3 and O4 hydroxyl groups. This approach provides a convenient method for identifying and quantifying the glycan pharmacophore and provides a novel method for interpreting glycan specificity that is independent of residue-level glycan nomenclature. A pharmacophore approach to defining specificity is readily transferable to molecular design software and, therefore, may be particularly useful in designing therapeutics (glycomimetics) that target GBPs.

Dataset Information

Defining the metal specificity of a multifunctional biofilm adhesion protein.

Publications

Defining the metal specificity of a multifunctional biofilm adhesion protein.

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