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A novel superfamily containing the beta-grasp fold involved in binding diverse soluble ligands.

ABSTRACT: BACKGROUND: Domains containing the beta-grasp fold are utilized in a great diversity of physiological functions but their role, if any, in soluble or small molecule ligand recognition is poorly studied. RESULTS: Using sensitive sequence and structure similarity searches we identify a novel superfamily containing the beta-grasp fold. They are found in a diverse set of proteins that include the animal vitamin B12 uptake proteins transcobalamin and intrinsic factor, the bacterial polysaccharide export proteins, the competence DNA receptor ComEA, the cob(I)alamin generating enzyme PduS and the Nqo1 subunit of the respiratory electron transport chain. We present evidence that members of this superfamily are likely to bind a range of soluble ligands, including B12. There are two major clades within this superfamily, namely the transcobalamin-like clade and the Nqo1-like clade. The former clade is typified by an insert of a beta-hairpin after the helix of the beta-grasp fold, whereas the latter clade is characterized by an insert between strands 4 and 5 of the core fold. CONCLUSION: Members of both clades within this superfamily are predicted to interact with ligands in a similar spatial location, with their specific inserts playing a role in the process. Both clades are widely represented in bacteria suggesting that this superfamily was derived early in bacterial evolution. The animal lineage appears to have acquired the transcobalamin-like proteins from low GC Gram-positive bacteria, and this might be correlated with the emergence of the ability to utilize B12 produced by gut bacteria. REVIEWERS: This article was reviewed by Andrei Osterman, Igor Zhulin, and Arcady Mushegian.

SUBMITTER: Burroughs AM

PROVIDER: S-EPMC1796856 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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A novel superfamily containing the beta-grasp fold involved in binding diverse soluble ligands.

Burroughs A Maxwell AM Balaji S S Iyer Lakshminarayan M LM Aravind L L

Biology direct 20070124

<h4>Background</h4>Domains containing the beta-grasp fold are utilized in a great diversity of physiological functions but their role, if any, in soluble or small molecule ligand recognition is poorly studied.<h4>Results</h4>Using sensitive sequence and structure similarity searches we identify a novel superfamily containing the beta-grasp fold. They are found in a diverse set of proteins that include the animal vitamin B12 uptake proteins transcobalamin and intrinsic factor, the bacterial polys ...[more]

PMID: 17250770

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Project description:BackgroundThe beta-grasp fold (beta-GF), prototyped by ubiquitin (UB), has been recruited for a strikingly diverse range of biochemical functions. These functions include providing a scaffold for different enzymatic active sites (e.g. NUDIX phosphohydrolases) and iron-sulfur clusters, RNA-soluble-ligand and co-factor-binding, sulfur transfer, adaptor functions in signaling, assembly of macromolecular complexes and post-translational protein modification. To understand the basis for the functional versatility of this small fold we undertook a comprehensive sequence-structure analysis of the fold and developed a natural classification for its members.ResultsAs a result we were able to define the core distinguishing features of the fold and numerous elaborations, including several previously unrecognized variants. Systematic analysis of all known interactions of the fold showed that its manifold functional abilities arise primarily from the prominent beta-sheet, which provides an exposed surface for diverse interactions or additionally, by forming open barrel-like structures. We show that in the beta-GF both enzymatic activities and the binding of diverse co-factors (e.g. molybdopterin) have independently evolved on at least three occasions each, and iron-sulfur-cluster-binding on at least two independent occasions. Our analysis identified multiple previously unknown large monophyletic assemblages within the beta-GF, including one which unifies versions found in the fasciclin-1 superfamily, the ribosomal protein L25, the phosphoribosyl AMP cyclohydrolase (HisI) and glutamine synthetase. We also uncovered several new groups of beta-GF domains including a domain found in bacterial flagellar and fimbrial assembly components, and 5 new UB-like domains in the eukaryotes.ConclusionEvolutionary reconstruction indicates that the beta-GF had differentiated into at least 7 distinct lineages by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions of the fold. The earliest beta-GF members were probably involved in RNA metabolism and subsequently radiated into various functional niches. Most of the structural diversification occurred in the prokaryotes, whereas the eukaryotic phase was mainly marked by a specific expansion of the ubiquitin-like beta-GF members. The eukaryotic UB superfamily diversified into at least 67 distinct families, of which at least 19-20 families were already present in the eukaryotic common ancestor, including several protein and one lipid conjugated forms. Another key aspect of the eukaryotic phase of evolution of the beta-GF was the dramatic increase in domain architectural complexity of proteins related to the expansion of UB-like domains in numerous adaptor roles.

Project description:BackgroundThe major birch pollen allergen, Bet v 1, is a member of the ubiquitous PR-10 family of plant pathogenesis-related proteins. In recent years, a number of diverse plant proteins with low sequence similarity to Bet v 1 was identified. In addition, determination of the Bet v 1 structure revealed the existence of a large superfamily of structurally related proteins. In this study, we aimed to identify and classify all Bet v 1-related structures from the Protein Data Bank and all Bet v 1-related sequences from the Uniprot database.ResultsStructural comparisons of representative members of already known protein families structurally related to Bet v 1 with all entries of the Protein Data Bank yielded 47 structures with non-identical sequences. They were classified into eleven families, five of which were newly identified and not included in the Structural Classification of Proteins database release 1.71. The taxonomic distribution of these families extracted from the Pfam protein family database showed that members of the polyketide cyclase family and the activator of Hsp90 ATPase homologue 1 family were distributed among all three superkingdoms, while members of some bacterial families were confined to a small number of species. Comparison of ligand binding activities of Bet v 1-like superfamily members revealed that their functions were related to binding and metabolism of large, hydrophobic compounds such as lipids, hormones, and antibiotics. Phylogenetic relationships within the Bet v 1 family, defined as the group of proteins with significant sequence similarity to Bet v 1, were determined by aligning 264 Bet v 1-related sequences. A distance-based phylogenetic tree yielded a classification into 11 subfamilies, nine exclusively containing plant sequences and two subfamilies of bacterial proteins. Plant sequences included the pathogenesis-related proteins 10, the major latex proteins/ripening-related proteins subfamily, and polyketide cyclase-like sequences.ConclusionThe ubiquitous distribution of Bet v 1-related proteins among all superkingdoms suggests that a Bet v 1-like protein was already present in the last universal common ancestor. During evolution, this protein diversified into numerous families with low sequence similarity but with a common fold that succeeded as a versatile scaffold for binding of bulky ligands.

Project description:A new family of dicopper(I) complexes [CuI2RL](X)2 (R=H, 1X, R=tBu, 2X and R=NO2, 3X, X=CF3SO3, ClO4, SbF6, or BArF, BArF=[B{3,5-(CF3)2C6H3}4]-), where RL is a Schiff-base ligand containing two tridentate binding sites linked by a xylyl spacer, has been prepared and characterized, and its reaction with O2 has been studied. The complexes were designed with the aim of reproducing structural aspects of the active site of type 3 dicopper proteins; they contain two three-coordinate copper sites and a rather flexible podand ligand backbone. The solid-state structures of 1ClO4, 2CF3SO3, 2ClO4, and 3BArF.CH3CN have been established by single-crystal X-ray diffraction analysis. 1ClO4 adopts a polymeric structure in the solid state while 2CF3SO3, 2ClO4, and 3BArF.CH3CN are monomeric. The complexes have been studied in solution by means of 1H and 19F NMR spectroscopy, which put forward the presence of dynamic processes. 1-3BArF and 1-3CF3SO3 in acetone react rapidly with O2 to generate metaestable [CuIII2(mu-O)2(RL)]2+ 1-3(O2) and [CuIII2(mu-O)2(CF3SO3)(RL)]+ 1-3(O2)(CF3SO3) species, respectively, that have been characterized by UV-vis spectroscopy and resonance Raman analysis. Instead, reaction of 1-3BArF with O2 in CH2Cl2 results in intermolecular O2 binding. DFT methods have been used to study the chemical identities and structural parameters of the O2 adducts, and the relative stability of the CuIII2(mu-O)2 form with respect to the CuII2(mu-eta2:eta2-O2) isomer. The reaction of 1X, X = CF3SO3 and BArF, with O2 in acetone has been studied by stopped-flow UV-vis exhibiting an unexpected very fast reaction rate (k=3.82(4)x10(3) M-1 s-1, DeltaH=4.9+/-0.5 kJ.mol-1, DeltaS=-148+/-5 J.K-1.mol-1), nearly 3 orders of magnitude faster than in the parent [CuI2(m-XYLMeAN)]2+. Thermal decomposition of 1-3(O2) does not result in aromatic hydroxylation. The mechanism and kinetics of O2 binding to 1X (X=CF3SO3 and BArF) are discussed and compared with those associated with selected examples of reported models of O2-processing copper proteins. A synergistic role of the copper ions in O2 binding and activation is clearly established from this analysis.

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A novel superfamily containing the beta-grasp fold involved in binding diverse soluble ligands.

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A novel superfamily containing the beta-grasp fold involved in binding diverse soluble ligands.

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