Hidden relationships between metalloproteins unveiled by structural comparison of their metal sites.

Yana Valasatava,Antonio Rosato,Claudia Andreini

doi:10.1038/srep09486

Abstract

Metalloproteins account for a substantial fraction of all proteins. They incorporate metal atoms, which are required for their structure and/or function. Here we describe a new computational protocol to systematically compare and classify metal-binding sites on the basis of their structural similarity. These sites are extracted from the MetalPDB database of minimal functional sites (MFSs) in metal-binding biological macromolecules. Structural similarity is measured by the scoring function of the available MetalS2 program. Hierarchical clustering was used to organize MFSs into clusters, for each of which a representative MFS was identified. The comparison of all representative MFSs provided a thorough structure-based classification of the sites analyzed. As examples, the application of the proposed computational protocol to all heme-binding proteins and zinc-binding proteins of known structure highlighted the existence of structural subtypes, validated known evolutionary links and shed new light on the occurrence of similar sites in systems at different evolutionary distances. The present approach thus makes available an innovative viewpoint on metalloproteins, where the functionally crucial metal sites effectively lead the discovery of structural and functional relationships in a largely protein-independent manner.

Highlights

Metalloproteins account for a substantial fraction of all proteins
The protocol leverages the organization of sites in equistructural groups (EGs hereafter) that is already provided by the MetalPDB database
Our definition of metal site extended beyond the metal ion and its aminoacidic ligands by involving all the chemical species containing at least one donor atom as well as all any other chemical species within a radius of 5.0 A

Summary

Introduction

Metalloproteins account for a substantial fraction of all proteins. They incorporate metal atoms, which are required for their structure and/or function. In this work we implemented and evaluated an approach based on the MetalS2 program to perform systematic, quantitative comparisons of MFS structures with the final aim of producing a classification of metal sites This is www.nature.com/scientificreports achieved by organizing MFSs into clusters in such a way that each cluster contains sites that are structurally similar to each other and differ from sites of the other clusters. MetalPDB shows that the iron coordination geometry in heme-containing MFSs is quite constant, being either square pyramidal or octahedral in the vast majority of cases, with four donor atoms out of a maximum of six provided by the porphyrin moiety This makes it difficult to exploit the features of the iron coordination for functional or structural classification. The application of our newly developed protocol can provide a means to verify structure similarities beyond the first coordination sphere, and their relationship to functional properties

Methods

Results

Conclusion