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Microenvironment analysis and identification of magnesium binding sites in RNA.

ABSTRACT: Interactions with magnesium (Mg2+) ions are essential for RNA folding and function. The locations and function of bound Mg2+ ions are difficult to characterize both experimentally and computationally. In particular, the P456 domain of the Tetrahymena thermophila group I intron, and a 58 nt 23s rRNA from Escherichia coli have been important systems for studying the role of Mg2+ binding in RNA, but characteristics of all the binding sites remain unclear. We therefore investigated the Mg2+ binding capabilities of these RNA systems using a computational approach to identify and further characterize their Mg2+ binding sites. The approach is based on the FEATURE algorithm, reported previously for microenvironment analysis of protein functional sites. We have determined novel physicochemical descriptions of site-bound and diffusely bound Mg2+ ions in RNA that are useful for prediction. Electrostatic calculations using the Non-Linear Poisson Boltzmann (NLPB) equation provided further evidence for the locations of site-bound ions. We confirmed the locations of experimentally determined sites and further differentiated between classes of ion binding. We also identified potentially important, high scoring sites in the group I intron that are not currently annotated as Mg2+ binding sites. We note their potential function and believe they deserve experimental follow-up.

SUBMITTER: Banatao DR

PROVIDER: S-EPMC169872 | biostudies-literature | 2003 Aug

REPOSITORIES: biostudies-literature

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Microenvironment analysis and identification of magnesium binding sites in RNA.

Banatao D Rey DR Altman Russ B RB Klein Teri E TE

Nucleic acids research 20030801 15

Interactions with magnesium (Mg2+) ions are essential for RNA folding and function. The locations and function of bound Mg2+ ions are difficult to characterize both experimentally and computationally. In particular, the P456 domain of the Tetrahymena thermophila group I intron, and a 58 nt 23s rRNA from Escherichia coli have been important systems for studying the role of Mg2+ binding in RNA, but characteristics of all the binding sites remain unclear. We therefore investigated the Mg2+ binding ...[more]

PMID: 12888505

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Project description:BACKGROUND: Magnesium research is increasing in molecular medicine due to the relevance of this ion in several important biological processes and associated molecular pathogeneses. It is still difficult to predict from the protein covalent structure whether a human chain is or not involved in magnesium binding. This is mainly due to little information on the structural characteristics of magnesium binding sites in proteins and protein complexes. Magnesium binding features, differently from those of other divalent cations such as calcium and zinc, are elusive. Here we address a question that is relevant in protein annotation: how many human proteins can bind Mg2+? Our analysis is performed taking advantage of the recently implemented Bologna Annotation Resource (BAR-PLUS), a non hierarchical clustering method that relies on the pair wise sequence comparison of about 14 millions proteins from over 300.000 species and their grouping into clusters where annotation can safely be inherited after statistical validation. RESULTS: After cluster assignment of the latest version of the human proteome, the total number of human proteins for which we can assign putative Mg binding sites is 3,751. Among these proteins, 2,688 inherit annotation directly from human templates and 1,063 inherit annotation from templates of other organisms. Protein structures are highly conserved inside a given cluster. Transfer of structural properties is possible after alignment of a given sequence with the protein structures that characterise a given cluster as obtained with a Hidden Markov Model (HMM) based procedure. Interestingly a set of 370 human sequences inherit Mg2+ binding sites from templates sharing less than 30% sequence identity with the template. CONCLUSION: We describe and deliver the "human magnesome", a set of proteins of the human proteome that inherit putative binding of magnesium ions. With our BAR-hMG, 251 clusters including 1,341 magnesium binding protein structures corresponding to 387 sequences are sufficient to annotate some 13,689 residues in 3,751 human sequences as "magnesium binding". Protein structures act therefore as three dimensional seeds for structural and functional annotation of human sequences. The data base collects specifically all the human proteins that can be annotated according to our procedure as "magnesium binding", the corresponding structures and BAR+ clusters from where they derive the annotation (http://bar.biocomp.unibo.it/mg).

Project description:BACKGROUND: For many metalloproteins, sequence motifs characteristic of metal-binding sites have not been found or are so short that they would not be expected to be metal-specific. Striking examples of such metalloproteins are those containing Mg2+, one of the most versatile metal cofactors in cellular biochemistry. Even when Mg2+-proteins share insufficient sequence homology to identify Mg2+-specific sequence motifs, they may still share similarity in the Mg2+-binding site structure. However, no structural motifs characteristic of Mg2+-binding sites have been reported. Thus, our aims are (i) to develop a general method for discovering structural patterns/motifs characteristic of ligand-binding sites, given the 3D protein structures, and (ii) to apply it to Mg2+-proteins sharing <30% sequence identity. Our motif discovery method employs structural alphabet encoding to convert 3D structures to the corresponding 1D structural letter sequences, where the Mg2+-structural motifs are identified as recurring structural patterns. RESULTS: The structural alphabet-based motif discovery method has revealed the structural preference of Mg2+-binding sites for certain local/secondary structures: compared to all residues in the Mg2+-proteins, both first and second-shell Mg2+-ligands prefer loops to helices. Even when the Mg2+-proteins share no significant sequence homology, some of them share a similar Mg2+-binding site structure: 4 Mg2+-structural motifs, comprising 21% of the binding sites, were found. In particular, one of the Mg2+-structural motifs found maps to a specific functional group, namely, hydrolases. Furthermore, 2 of the motifs were not found in non metalloproteins or in Ca2+-binding proteins. The structural motifs discovered thus capture some essential biochemical and/or evolutionary properties, and hence may be useful for discovering proteins where Mg2+ plays an important biological role. CONCLUSION: The structural motif discovery method presented herein is general and can be applied to any set of proteins with known 3D structures. This new method is timely considering the increasing number of structures for proteins with unknown function that are being solved from structural genomics incentives. For such proteins, which share no significant sequence homology to proteins of known function, the presence of a structural motif that maps to a specific protein function in the structure would suggest likely active/binding sites and a particular biological function.

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Microenvironment analysis and identification of magnesium binding sites in RNA.

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Microenvironment analysis and identification of magnesium binding sites in RNA.

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