Lanmodulin: A Highly Selective Lanthanide-Binding Protein from a Lanthanide-Utilizing Bacterium

Abstract

Lanthanides (Lns) have been shown recently to be essential cofactors in certain enzymes in methylotrophic bacteria. Here we identify in the model methylotroph, Methylobacterium extorquens, a highly selective Ln^III-binding protein, which we name lanmodulin (LanM). LanM possesses four metal-binding EF hand motifs, commonly associated with Ca^II-binding proteins. In contrast to other EF hand-containing proteins, however, LanM undergoes a large conformational change from a largely disordered state to a compact, ordered state in response to picomolar concentrations of all Ln^III (Ln = La-Lu, Y), whereas it only responds to Ca^II at near-millimolar concentrations. Mutagenesis of conserved proline residues present in LanM's EF hands, not encountered in Ca^II-binding EF hands, to alanine pushes Ca^II responsiveness into the micromolar concentration range while retaining picomolar Ln^III affinity, suggesting that these unique proline residues play a key role in ensuring metal selectivity in vivo. Identification and characterization of LanM provides insights into how biology selectively recognizes low-abundance Ln^III over higher-abundance Ca^II, pointing toward biotechnologies for detecting, sequestering, and separating these technologically important elements.