Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38.
Human CD38 is a multifunctional ectoenzyme responsible for catalyzing the conversions from nicotinamide adenine dinucleotide (NAD) to cyclic ADP-ribose (cADPR) and from cADPR to ADP-ribose (ADPR). Both cADPR and ADPR are calcium messengers that can mobilize intracellular stores and activate influx as well. In this study, we determined three crystal structures of the human CD38 enzymatic domain complexed with cADPR at 1.5-A resolution, with its analog, cyclic GDP-ribose (cGDPR) (1.68 A) and with NGD (2.1 A) a substrate analog of NAD. The results indicate that the binding of cADPR or cGDPR to the active site induces structural rearrangements in the dipeptide Glu(146)-Asp(147) by as much as 2.7 A) providing the first direct evidence of a conformational change at the active site during catalysis. In addition, Glu(226) is shown to be critical not only in catalysis but also in positioning of cADPR at the catalytic site through strong hydrogen bonding interactions. Structural details obtained from these complexes provide a step-by-step description of the catalytic processes in the synthesis and hydrolysis of cADPR.
Liu
Qun
Q
MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, New York 14853, USA.
Kriksunov
Irina A
IA
Graeff
Richard
R
Lee
Hon Cheung
HC
Hao
Quan
Q
D051997:ADP-ribosyl Cyclase 1 / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002384:Catalysis; D018360:Crystallography, X-Ray; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D008562:Membrane Glycoproteins; D009243:NAD; D036563:Cyclic ADP-Ribose; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1