title: 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.
  
  
  CONCLUSIONS
  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.
  
  
  METHODS
  This article was reviewed by Andrei Osterman, Igor Zhulin, and Arcady Mushegian.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. burrough@ncbi.nlm.nih.gov
authors.forename: A Maxwell
authors.initials: AM
authors.lastname: Burroughs
authors.forename: S
authors.initials: S
authors.lastname: Balaji
authors.forename: Lakshminarayan M
authors.initials: LM
authors.lastname: Iyer
authors.forename: L
authors.initials: L
authors.lastname: Aravind