Abstract
Zinc is indispensable to all forms of life as it is an essential component of many different proteins involved in a wide range of biological processes. Not differently from other metals, zinc in proteins can play different roles that depend on the features of the metal-binding site. In this work, we describe zinc sites in proteins with known structure by means of three-dimensional templates that can be automatically extracted from PDB files and consist of the protein structure around the metal, including the zinc ligands and the residues in close spatial proximity to the ligands. This definition is devised to intrinsically capture the features of the local protein environment that can affect metal function, and corresponds to what we call a minimal functional site (MFS). We used MFSs to classify all zinc sites whose structures are available in the PDB and combined this classification with functional annotation as available in the literature. We classified 77% of zinc sites into ten clusters, each grouping zinc sites with structures that are highly similar, and an additional 16% into seven pseudo-clusters, each grouping zinc sites with structures that are only broadly similar. Sites where zinc plays a structural role are predominant in eight clusters and in two pseudo-clusters, while sites where zinc plays a catalytic role are predominant in two clusters and in five pseudo-clusters. We also analyzed the amino acid composition of the coordination sphere of zinc as a function of its role in the protein, highlighting trends and exceptions. In a period when the number of known zinc proteins is expected to grow further with the increasing awareness of the cellular mechanisms of zinc homeostasis, this classification represents a valuable basis for structure-function studies of zinc proteins, with broad applications in biochemistry, molecular pharmacology and de novo protein design.
Highlights
Zinc is an essential element for living organisms
All the available protein structures containing zinc were downloaded from the Protein Data Bank (PDB) [22] by searching for entries that contained any of the following non-standard PDB residues: BAZ, BOZ, DAZ, DOZ, DTZ, HE5, HES, ZEM, ZH3, ZN, ZN2, ZN3, ZNH, ZNO, and ZO3
Non-physiological Zn-sites were identified and discarded, resulting in the removal of 4832 Zn-sites and 1288 Zn-structures from the original dataset. This result highlights the importance of considering the physiological relevance of zinc atoms bound to proteins, as more than 20% of PDB structures containing zinc are not zinc proteins
Summary
Zinc is an essential element for living organisms While this statement applies to several other metals, the pervasive occurrence of zinc in biological processes is unique. In eukaryotes but not in prokaryotes the majority of zinc proteins function in the regulation of gene expression, pointing out that the biological importance of zinc increased as increasingly complex cellular, and in particular multicellular, systems evolved. Many of these proteins contain one or more so-called zinc fingers, which are small protein domains stabilized by a zinc ion playing a structural role [7]. As the molecular mechanisms of cellular zinc homeostasis are just beginning to be elucidated, the number of these proteins and the size of zinc proteomes is likely to be larger than what is currently realized [9,10]
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