Abstract
Protein sequence similarity networks (SSNs) constitute a convenient approach to analyze large polypeptide sequence datasets, and have been successfully applied to study a number of protein families over the past decade. SSN analysis is herein combined with traditional cladistic and phenetic phylogenetic analysis (respectively based on multiple sequence alignments and all-against-all three-dimensional protein structure comparisons) in order to assist the ancestral reconstruction and integrative revision of the superfamily of metallo-β-lactamases (MBLs). It is shown that only 198 out of 15,292 representative nodes contain at least one experimentally obtained protein structure in the Protein Data Bank or a manually annotated SwissProt entry, that is to say, only 1.3 % of the superfamily has been functionally and/or structurally characterized. Besides, neighborhood connectivity coloring, which measures local network interconnectivity, is introduced for detection of protein families within SSN clusters. This approach provides a clear picture of how many families remain unexplored in the superfamily, while most MBL research is heavily biased towards a few families. Further research is suggested in order to determine the SSN topological properties, which will be instrumental for the improvement of automated sequence annotation methods.
Highlights
The metallo-β-lactamase (MBL) superfamily comprises an ancient group of proteins found in all domains of life, sharing a distinctive αββα fold with a histidine-rich motif for binding of transition metal ions
Despite the divergence of primary structure, the threedimensional fold of polypeptides is less sensitive to mutational events, retaining evolutionary information encoded in the arrangement of secondary structure elements
The amino acid sequences of those 105 polypeptides were retrieved and aligned to construct a maximum-likelihood multiple sequence alignment (MSA)-based bootstrapped unrooted consensus cladogram, whose topology reflects the sequence homology relationships between extant taxa according to a specific evolutionary model
Summary
The metallo-β-lactamase (MBL) superfamily comprises an ancient group of proteins found in all domains of life, sharing a distinctive αββα fold with a histidine-rich motif for binding of transition metal ions. BcII and ZBLs in general were believed to use a single Zn(II) ion to activate a water molecule for hydrolysis, paralleling the mechanism by which carbonic anhydrases catalyze carbon dioxide hydration. This hypothesis was soon questioned when the structure of ZBL CcrA from Bacteroides fragilis was published, disclosing a bimetallic zinc center, with the second zinc being coordinated to nearby Asp, Cys and His residues [2]. It was found that monometallic ZBLs are rather exceptional and the hydrolysis reaction generally requires two Zn(II) ions [6, 7]
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