Divalent d-block metal cations (DDMCs), such as Fe, Zn and Mn, participate in many biological processes. Understanding how specific DDMCs are transported to and within the cell and what controls their binding selectivity to different proteins is crucial for defining the mechanisms of metalloproteins. To better understand such processes, we scanned the RCSB Protein Data Bank, performed a de novo structural-based comprehensive analysis of seven DDMCs and found their amino acid binding and coordination geometry propensities. We then utilized these results to characterize the correlation between metal selectivity, specific binding site composition and phylogenetic classification of the cation diffusion facilitator (CDF) protein family, a family of DDMC transporters found throughout evolution and sharing a conserved structure, yet with different members displaying distinct metal selectivity. Our analysis shows that DDMCs differ, at times significantly, in terms of their binding propensities, and that in each CDF clade, the metal selectivity-related binding site has a unique and conserved sequence signature. However, only limited correlation exists between the composition of the DDMC binding site in each clade and the metal selectivity shown by its proteins.

Few cerebro-renal syndromes have been described to date. Perez et al. identify a novel autosomal recessive cerebro-renal syndrome in a consanguineous Bedouin kindred, caused by a mutation in SLC30A9. The mutation disrupts the role of SLC30A9 in Zn2+ transport, leading to impaired regulation of cytosolic zinc homeostasis.

Cation diffusion facilitator (CDF) proteins are a conserved family of transmembrane transporters that ensure cellular homeostasis of divalent transition metal cations. Metal cations bind to CDF protein's cytoplasmic C‐terminal domain (CTD), leading to closure from its apo open V‐shaped dimer to a tighter packed structure, followed by a conformational change of the transmembrane domain, thus enabling transport of the metal cation. By implementing a comprehensive range of biochemical and biophysical methods, we studied the molecular mechanism of metal binding to the magnetotactic bacterial CDF protein MamM CTD. Our results reveal that the CTD is rather dynamic in its apo form, and that two dependent metal‐binding sites, a single central binding site and two symmetrical, peripheral sites, are available for metal binding. However, only cation binding to the peripheral sites leads to conformational changes that lock the protein in a compact state. Thus, this work reveals how metal binding is regulating the sequential uptakes of metal cations by MamM, and extends our understanding of the complex regulation mechanism of CDF proteins. Database Structural data are available in RCSB Protein Data Bank under the accession numbers: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6G64, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6G55, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6G5E and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6G6I (for CS, C267S, CS‐C267S and W247A, respectively).

White-rot fungi secrete a repertoire of high-redox potential oxidoreductases to efficiently decompose lignin. Of these enzymes, versatile peroxidases (VPs) are the most promiscuous biocatalysts. VPs are attractive enzymes for research and industrial use but their recombinant production is extremely challenging. To date, only a single VP has been structurally characterized and optimized for recombinant functional expression, stability, and activity. Computational enzyme optimization methods can be applied to many enzymes in parallel but they require accurate structures. Here, we demonstrate that model structures computed by deep-learning-based ab initio structure prediction methods are reliable starting points for one-shot PROSS stability-design calculations. Four designed VPs encoding as many as 43 mutations relative to the wildtype enzymes are functionally expressed in yeast, whereas their wildtype parents are not. Three of these designs exhibit substantial and useful diversity in their reactivity profiles and tolerance to environmental conditions. The reliability of the new generation of structure predictors and design methods increases the scale and scope of computational enzyme optimization, enabling efficient discovery and exploitation of the functional diversity in natural enzyme families directly from genomic databases.

Magnetosomes are protein-rich membrane organelles that encapsulate magnetite or greigite and whose chain alignment enables magnetotactic bacteria (MTB) to sense the geomagnetic field. As these bacteria synthesize uniform magnetic particles, their biomineralization mechanism is of great interest among researchers from different fields, from material engineering to medicine. Both magnetosome formation and magnetic particle synthesis are highly controlled processes that can be divided into several crucial steps: membrane invagination from the inner-cell membrane, protein sorting, the magnetosomes' arrangement into chains, iron transport, chemical environment regulation of the magnetosome lumen, magnetic particle nucleation, and finally crystal growth, size, and morphology control. This complex system involves an ensemble of unique proteins that participate in different stages during magnetosome formation, some of which were extensively studied in recent years. Here, we present the current knowledge on magnetosome biosynthesis with a focus on the different proteins and the main biochemical pathways along this process.