Sequence and Structural Links between Distant ADP-Ribosyltransferase Families
The low resolution structure of the Pseudomonas aeroginosa exotoxin A (ETA) presented in 1986 provided the first tantalizing three-dimensional view of an ADP-ribosyltransferase (ADPRT) catalytic domain. The major features of this protein fold have recurred in the more recently solved crystal structures of the cholera toxin-related heatlabile enterotoxin (LT), diphtheria toxin (DT) and pertussis toxin (PT). A core set of α+β elements define a minimal, conserved scaffold with remarkably plastic sequence requirements - only a single glutamic acid residue critical to catalytic activity is invariant. Other interchangeable residues in locations important for catalysis and binding are suggested by the cocrystal structures of DT with the inhibitor ApUp, ETA with bound AMP and nicotinamide, and DT with substrate NAD - in close accord with labeling and mutagenic data. Faint sequence resemblances that were earlier noticed among prokaryotic ADPRTs have now been securely extended by the structural concordance between toxin folds; more recently, eukaryotic ADPRTs have surfaced and their sequences can be reliably threaded into the conserved core fold. We will briefly summarize efforts in Palo Alto and Hamburg to explore these latter relationships, and to mount a rigorous search for new ADPRT families in the growing sequence databases.
KeywordsCatalysis Explosive Disulfide Pseudomonas Adenine
Unable to display preview. Download preview PDF.
- 14.Sixma, T.K., S.E. Pronk, K.H. Kalk, E.S. Wartna, B.A.M. Van Zanten, B. Witholt, W.G.J. Hol. 1991. Crystal structure of a cholera toxin-related heat-labile enterotoxin from E. coli. Nature 351: 371–377.Google Scholar
- 22.Koch-Nolte, F., D. Petersen, S. Balasubramanian, F. Haag, D. Kahlke, T. Wilier, R. Kastelein, J.F. Bazan, H.G. Thiele. 1996. Mouse T cell membrane proteins Rt6-1 and Rt6-2 are arginine/protein mono(ADPribosyl) transferases and share secondary structure motifs with ADP-ribosylating bacterial toxins. J. Biol. Chem. 271: 7686–7693.PubMedCrossRefGoogle Scholar
- 29.Li, M., F. Dyda, I. Benhar, I. Pastan, D.R. Davies. 1996. Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation. Proc. Natl. Acad. Sci. USA 93: 6902–6906.PubMedCrossRefGoogle Scholar