TY - JOUR
T1 - The ARTT motif and a unified structural understanding of substrate recognition in ADP-ribosylating bacterial toxins and eukaryotic ADP-ribosyltransferases
AU - Han, Seungil
AU - Tainer, John A.
N1 - Funding Information:
Acknowledgements. We thank Novartis Agribusiness Biotechnology Research Inc. for initiation of the structural studies of C3 toxin and the Skaggs Institute for Research for fellowship support (S. Han).
PY - 2001
Y1 - 2001
N2 - ADP-ribosylation is a widely occurring and biologically critical covalent chemical modification process in pathogenic mechanisms, intracellular signaling systems, DNA repair, and cell division. The reaction is catalyzed by ADP-ribosyltransferases, which transfer the ADP-ribose moiety of NAD to a target protein with nicotinamide release. A family of bacterial toxins and eukaryotic enzymes has been termed the mono-ADP-ribosyltransferases, in distinction to the poly-ADP-ribosyltransferases, which catalyze the addition of multiple ADP-ribose groups to the carboxyl terminus of eukaryotic nucleoproteins. Despite the limited primary sequence homology among the different ADP-ribosyltransferases, a central cleft bearing the NAD-binding pocket formed by the two perpendicular β-sheet cores has been remarkably conserved between bacterial toxins and eukaryotic mono- and poly-ADP-ribosyltransferases. The majority of bacterial toxins and eukaryotic mono-ADP-ribosyltransferases are characterized by conserved His and catalytic Glu residues. In contrast, diphtheria toxin, Pseudomonas exotoxin A, and eukaryotic poly-ADP-ribosytransferases are characterized by conserved Arg and catalytic Glu residues. Structural and mutagenic studies of the NAD-binding core of a binary toxin and a C3-like toxin identified an ARTT motif (ADP-ribosylating turn-turn motif) that is implicated in substrate specificity and recognition. Here we apply structure-based sequence alignment and comparative structural analyses of all known structures of ADP-ribosyltransfeases to suggest that this ARTT motif is functionally important in many ADP-ribosylating enzymes that bear a NAD-binding cleft as characterized by conserved Arg and catalytic Glu residues. Overall, structure-based sequence analysis reveals common core structures and conserved active sites of ADP-ribosyltransferases to support similar NAD-binding mechanisms but differing mechanisms of target protein binding via sequence variations within the ARTT motif structural framework. Thus, we propose here that the ARTT motif represents an experimentally testable general recognition motif region for many ADP-ribosyltransferases and thereby potentially provides a unified structural understanding of substrate recognition in ADP-ribosylation processes.
AB - ADP-ribosylation is a widely occurring and biologically critical covalent chemical modification process in pathogenic mechanisms, intracellular signaling systems, DNA repair, and cell division. The reaction is catalyzed by ADP-ribosyltransferases, which transfer the ADP-ribose moiety of NAD to a target protein with nicotinamide release. A family of bacterial toxins and eukaryotic enzymes has been termed the mono-ADP-ribosyltransferases, in distinction to the poly-ADP-ribosyltransferases, which catalyze the addition of multiple ADP-ribose groups to the carboxyl terminus of eukaryotic nucleoproteins. Despite the limited primary sequence homology among the different ADP-ribosyltransferases, a central cleft bearing the NAD-binding pocket formed by the two perpendicular β-sheet cores has been remarkably conserved between bacterial toxins and eukaryotic mono- and poly-ADP-ribosyltransferases. The majority of bacterial toxins and eukaryotic mono-ADP-ribosyltransferases are characterized by conserved His and catalytic Glu residues. In contrast, diphtheria toxin, Pseudomonas exotoxin A, and eukaryotic poly-ADP-ribosytransferases are characterized by conserved Arg and catalytic Glu residues. Structural and mutagenic studies of the NAD-binding core of a binary toxin and a C3-like toxin identified an ARTT motif (ADP-ribosylating turn-turn motif) that is implicated in substrate specificity and recognition. Here we apply structure-based sequence alignment and comparative structural analyses of all known structures of ADP-ribosyltransfeases to suggest that this ARTT motif is functionally important in many ADP-ribosylating enzymes that bear a NAD-binding cleft as characterized by conserved Arg and catalytic Glu residues. Overall, structure-based sequence analysis reveals common core structures and conserved active sites of ADP-ribosyltransferases to support similar NAD-binding mechanisms but differing mechanisms of target protein binding via sequence variations within the ARTT motif structural framework. Thus, we propose here that the ARTT motif represents an experimentally testable general recognition motif region for many ADP-ribosyltransferases and thereby potentially provides a unified structural understanding of substrate recognition in ADP-ribosylation processes.
KW - ADP-ribosylation
KW - ADP-ribosyltransferase
KW - ARTT motif
KW - Catalytic mechanism
KW - NAD
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U2 - 10.1078/1438-4221-00162
DO - 10.1078/1438-4221-00162
M3 - Article
C2 - 11890553
AN - SCOPUS:0036196923
SN - 1438-4221
VL - 291
SP - 523
EP - 529
JO - International Journal of Medical Microbiology
JF - International Journal of Medical Microbiology
IS - 6-7
ER -